Methods and systems for treating diabetes and related diseases and disorders

ABSTRACT

Systems, device and methods treat target tissue to provide a therapeutic benefit to the patient. A tissue treatment device comprises a tissue treatment element constructed and arranged to treat target tissue, such as duodenal mucosa tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/406,572 (Attorney Docket No. 41714-713.301), filed Jan. 13, 2017,which is a continuation of PCT Application No. PCT/US2015/040775(Attorney Docket No. 41714-713.601), filed Jul. 16, 2015, which claimsthe benefit of U.S. Provisional Application No. 62/025,307 (AttorneyDocket No. 41714-713.101), filed Jul. 16, 2014, the entire content ofwhich are incorporated herein by reference.

This application is related to: U.S. patent application Ser. No.13/945,138, entitled “Devices and Methods for the Treatment of Tissue”,filed Jul. 18, 2013; U.S. patent application Ser. No. 14/470,503,entitled “Heat Ablation Systems, Devices and Methods for the Treatmentof Tissue, filed Aug. 27, 2014; U.S. patent application Ser. No.14/515,324, entitled “Tissue Expansion Devices, Systems and Methods”,filed Oct. 15, 2014; U.S. patent application Ser. No. 14/609,332,entitled “Electrical Energy Ablation Systems, Devices and Methods forthe Treatment of Tissue”, filed Jan. 29, 2015; U.S. patent applicationSer. No. 14/609,334, entitled “Ablation Systems, Devices and Methods forthe Treatment of Tissue”, filed Jan. 29, 2015; U.S. patent applicationSer. No. 14/673,565, entitled “Methods, Systems and Devices forPerforming Multiple Treatments on a Patient”, filed Mar. 30, 2015;International Patent Application Serial Number PCT/US2014/040957,entitled “Methods, Systems and Devices for Reducing the Luminal SurfaceArea of the Gastrointestinal Tract”, filed Jun. 4, 2014; InternationalPatent Application Serial Number PCT/US2014/055514, entitled “Systems,Methods and Devices for Treatment of Target Tissue”, filed Sep. 12,2014; International Patent Application Serial Number PCT/US2014/066829,entitled “Systems, Devices and Methods for the Creation of a TherapeuticRestriction in the Gastrointestinal Tract”, filed Nov. 21, 2014;International Patent Application Serial Number PCT/US2015/022293,entitled “Injectate Delivery Devices, Systems and Methods”, filed Mar.24, 2015; the entire contents of each are incorporated herein byreference in their entirety.

TECHNICAL FIELD

The embodiments disclosed herein relate generally to methods, systems,and devices for treating a patient, particularly for treating tissue ofthe gastrointestinal tract to provide a therapy.

BACKGROUND OF THE INVENTION

The current paradigm for medical therapy for type 2 diabetes begins withimprovements in diet and exercise. The vast majority of patients do notachieve sustained good glycemic control with lifestyle changes alone.Several classes of pharmacologic therapy are available, including drugsthat increase insulin secretion from the pancreas, drugs that enhancethe body's sensitivity to insulin, and a variety of other drug classes.Despite these oral therapies, diabetes control will usually deteriorateover time and treatment with insulin will become necessary. All told,however, a large proportion of patients remain poorly controlled despiteall of these measures.

There are many reasons for the limited effectiveness of currentpharmacologic interventions in the general population. First, today'smedicines may lower blood sugar but they do not address the fundamentalpathogenesis of Type 2 Diabetes. Second, poor compliance to complicatedpharmacologic regimens is well documented and a structural barrier tobetter glycemic control. Third, clinical inertia on the part ofphysicians prevents drug regimen escalation even in patients with accessto excellent medical care. Fourth, psychological resistance to insulinprevents the use of this class of agents. Fifth, hypoglycemia (and therisk thereof) limits the degree of pharmacologic intervention with whichphysicians and patients feel comfort. Taken together, nearly 50% ofpatients remain poorly controlled throughout Europe and the UnitedStates.

Interestingly, certain forms of bariatric surgery have a profoundanti-diabetic effect in ways that clinicians have only begun toappreciate and characterize. Though the mechanisms underlying thisimprovement in glucose homeostasis are not completely understood,certain compelling observations have been made. In particular, surgeriesthat divert the passage of nutrients around the duodenum (or firstportion of the small intestine) appear to lead to nearly immediate,extremely durable, and weight-independent anti-diabetic effects. Becausethe GI tract is the largest endocrine organ in the body, the bypass ofthe proximal small bowel leads to hormonal changes that improve glucosehomeostasis. This effect appears to occur without substantial changes inabsorption from the intestine. Rather, these hormonal changes restorethe ability of the liver and muscle to suppress endogenous glucoseproduction in response to insulin, a physiologic process that isotherwise impaired in patients with diabetes.

There are two main theories as to why bypass of the proximal small bowelexert such a strong anti-diabetic effect, both of which are likely atleast partial contributors. First, some believe that the delivery ofexcess nutrients to the distal small bowel leads to enhanced secretionof GLP-1 (and perhaps additional related insulin secreting hormones)from the GLP-1-rich entero-endocrine cells of the terminal ileum andcolon. Enhanced GLP-1 release into the blood stream after an ingestedmeal has a number of beneficial effects on glucose homeostasis. A secondtheory is that patients with diabetes acquire mucosal alterations intheir proximal small bowel that contribute to insulin resistance andglucose intolerance. Data from rats and humans suggest that prolongedexposure to a Western diet leads to an increase in enteroendocrine cellnumbers and subsequent gastric inhibitory peptide (GIP) after a meal.Other studies have demonstrated hypertrophy of the mucosa of the smallbowel in patients with diabetes. In this way, the body's insulinresistance arises from hormones produced by the proximal small bowel asa consequence of these mucosal alterations. Bypass of nutrients aroundthe duodenum prevents the release of these hormones and thereforeimmediately leads to an improvement in glucose tolerance after surgery.

Unfortunately, as effective as these bariatric surgeries are, one cannotimagine that surgery can be offered to enough patients to adequatelyaddress the diabetes pandemic. There are several reasons for thislimitation. The primary indication for bariatric surgery remains morbidobesity, yet most diabetics are not morbidly obese. Also, the risks (ofmajor morbidity, mortality, and need for re-operation) from bypasssurgeries are quite real and pose a significant barrier to its wholesaleadoption as a treatment for type 2 diabetes. Finally, surgery isinvasive, psychologically difficult, and physically demanding. For allthese reasons, only a minority of patients with diabetes currentlyundergoes surgery as a treatment for their diabetes.

For these and other reasons, there is a need for improved systems,devices and method for the treatment of diabetes and similar patientdiseases and disorders.

SUMMARY

According to one aspect of the present inventive concepts, a system fortreating target tissue comprises a tissue treatment device comprising atissue treatment element constructed and arranged to treat targettissue, the target tissue comprising duodenal mucosa. The system isconstructed and arranged to provide a therapeutic benefit to thepatient, such as to treat diabetes or another patient disease ordisorder.

In some embodiments, the system is configured to counteract duodenalmucosal changes that cause an intestinal hormonal impairment leading toinsulin resistance in patients.

In some embodiments, the system is configured to improve the body'sability to process sugar and/or to improve glycemic control in patientswith insulin resistance and/or Type 2 diabetes.

In some embodiments, the system is configured to treat diabetes.

In some embodiments, the system is configured to treathypercholesterolemia.

In some embodiments, the system is configured to treat at least one of adisease or disorder selected from the group consisting of: diabetes;pre-diabetes; impaired glucose tolerance; insulin resistance; obesity orotherwise being overweight; a metabolic disorder and/or disease; andcombinations thereof.

In some embodiments, the system is configured to treat at least one of adisease or disorder selected from the group consisting of: Type 2diabetes; Type 1 diabetes; “Double diabetes”; gestational diabetes;hyperglycemia; pre-diabetes; impaired glucose tolerance; insulinresistance; non-alcoholic fatty liver disease (NAFLD); non-alcoholicsteatohepatitis (NASH); obesity; obesity-related disorder; polycysticovarian syndrome; hypertriglyceridemia; hypercholesterolemia; psoriasis;GERD; coronary artery disease; stroke; TIA; cognitive decline; dementia;diabetic nephropathy; neuropathy; retinopathy; diabetic heart disease;diabetic heart failure; and combinations thereof.

In some embodiments, the system is configured to treat two or more of:Type 2 diabetes; Type 1 diabetes; “Double diabetes”; gestationaldiabetes; hyperglycemia; pre-diabetes; impaired glucose tolerance;insulin resistance; non-alcoholic fatty liver disease (NAFLD);non-alcoholic steatohepatitis (NASH); obesity; obesity-related disorder;polycystic ovarian syndrome; hypertriglyceridemia; hypercholesterolemia;psoriasis; GERD; coronary artery disease; stroke; TIA; cognitivedecline; dementia; diabetic nephropathy; neuropathy; retinopathy;diabetic heart disease; and diabetic heart failure.

In some embodiments, the system is configured to avoid treatment ofnon-target tissue. The non-target tissue can comprise the ampulla ofVater. The non-target tissue can comprise tissue selected from the groupconsisting of: gastrointestinal adventitia; duodenal adventitia; thetunica serosa; the tunica muscularis; the outermost partial layer of thesubmucosa; ampulla of Vater; pancreas; bile duct; pylorus; andcombinations thereof.

In some embodiments, the target tissue comprises at least two axialsegments of duodenal mucosa, and the therapeutic benefit results fromthe treatment of the at least two axial segments by the tissue treatmentelement. Each axial segment can comprise a length between approximately1.9 cm and 3.3 cm. Each axial segment can comprise a length ofapproximately 3 cm. The target tissue can comprise an approximately fullcircumferential portion of each axial segment (i.e. approximately 360°of the mucosal layer of each axial segment) or a partial circumferentialportion of each axial segment (i.e. less than 360° of the mucosal layerof each axial segment).

In some embodiments, the target tissue comprises at least four (full orpartial circumferential) axial segments of duodenal mucosa, and thetherapeutic benefit results from the treatment of the at least fouraxial segments by the tissue treatment element. The target tissue cancomprise at least six axial segments of duodenal mucosa, and thetherapeutic benefit results from the treatment of the at least six axialsegments by the tissue treatment element. Each axial segment cancomprise a length between approximately 0.7 cm and 2.0 cm.

In some embodiments, the system is configured to cause a therapeuticbenefit selected from the group consisting of: improvement in HbA1c,fasting glucose and/or post-prandial glucose; at least a 1% improvementin HbA1c; a resultant HbA1c of less than 7.5%, less than 7.0%, less than6.5%, or less than 6.0%; improvement in one or more triglyceride levels;improvement in AST, ALT, liver fibrosis panel, liver fibrosis score,NAFLD assessment and/or or NASH assessment; improvement in risk ofmyocardial infarction, stroke, TIA and/or peripheral vascular disease ordiabetic cardiomyopathy; improvement in microvascular disease risk suchas nephropathy, retinopathy and/or neuropathy; reduced development ofend-stage renal disease, blindness and/or amputation; reduced insulinrequirement (e.g. in patients with insulin-dependent diabetes) or otherinjectable therapy requirement; reduced medication requirement (e.g. inpatients with diabetes) either in number of medicines or dosage ofmedicines; improved fetal birth outcomes (e.g. in patients withgestational diabetes); improved fertility in patients with polycysticovarian syndrome and/or reduced hirsutism; weight loss of at least 5% ofexcess body weight, or at least 10%, 20%, 30% or 40% of excess bodyweight; reduced blood pressure; reduced cardiovascular risk; improveddiabetes control and/or reduced diabetic complications; reduced obesityand/or reduced weight; reduced cognitive decline or prevention ofdementia; and combinations thereof. The therapeutic benefit can have aclinically significant durability of at least 3 months. The therapeuticbenefit can have a clinically significant durability of at least 6months, or at least 1 year.

In some embodiments, the system is configured to reduce the HbA1c levelof the patient. The system can be configured to cause an HbA1c reductionof approximately 2.18%. The system can be configured to cause an HbA1creduction of at least 0.7%. The system can be configured to cause anHbA1c reduction of at least 1.0%. The system can be configured to causean HbA1c reduction of at least 1.5%. The system can be configured tocause an HbA1c reduction of at least 2.0%. The system can be configuredto cause an HbA1c reduction of at least 2.5%. The system can beconfigured to reduce HbA1c to a target level less than or equal to 7.5%.The system can be configured to reduce HbA1c to a target level less thanor equal to 7.0%. The system can be configured to reduce HbA1c to atarget level less than or equal to 5.5%. The system can be configured tocause an HbA1c level below 7.5% at least 150 days after performance ofthe target tissue treatment.

In some embodiments, the system is configured to reduce FPG. The systemcan be configured to cause an FPG reduction of approximately 63.5 mg/dl.The system can be configured to reduce FPG to a target level less thanor equal to 150 mg/dl. The system can be configured to reduce FPG to atarget level less than or equal to 126 mg/dl. The system can beconfigured to reduce FPG to a target level less than or equal to 100mg/dl.

In some embodiments, the system is configured to improve fasting glucoseand/or HbA1c without causing a significant decline in fasting insulinand/or post-prandial insulin.

In some embodiments, the system is configured to improve beta cellinsulin secretory capacity for at least 3 months. The system can beconfigured to improve beta cell insulin secretory capacity for at least6 months, or at least 1 year.

In some embodiments, the system is configured to prevent the decline ofbeta cell insulin secretory capacity for at least 3 months.

In some embodiments, the system is configured to reduce 2hPG. The systemcan be configured to cause a 2hPH reduction of approximately 103.7mg/dl. The system can be configured to reduce 2hPG to a target levelless than or equal to 250 mg/dl. The system can be configured to reduce2hPG to a target level less than or equal to 200 mg/dl. The system canbe configured to reduce 2hPG to a target level less than or equal to 175mg/dl.

In some embodiments, the system is configured to provide an improvementin a patient condition as measured by the SF-36 Health Survey. Theimprovement can comprise an improvement in the Mental Change score ofthe SF-36 Health Survey. The improvement can comprise a score change ofat least 3 points, or at least 5 points. The improvement can comprise ascore change of at least 10 points.

In some embodiments, the system is configured to provide a reduction inexcess body weight of the patient. The reduction can comprise areduction of at least 5% of excess body weight. The reduction cancomprise a reduction of at least 10% of excess body weight. Thereduction can comprise a reduction of at least 20% of excess bodyweight. The reduction can comprise a reduction of at least 30% of excessbody weight. The reduction can comprise a reduction of at least 40% ofexcess body weight.

In some embodiments, the system is configured to treat a patient with aduration of diabetes less than 10 years.

In some embodiments, the system is configured to treat a patient with anage between 18 years and 75 years.

In some embodiments, the system is configured to treat a patient with anage between 5 years and 18 years.

In some embodiments, the system is configured to treat a patient with aBMI between 22 and 60.

In some embodiments, the system is configured to treat a patient with anHbA1c between 6.0% and 12.0%. The system can be configured to treat apatient with an HbA1c between 7.5% and 12.0%. The system can beconfigured to treat a patient with an HbA1c between 7.5% and 10.0%, suchas between 7.5% and 9.0%.

In some embodiments, the target tissue further comprises non-duodenalmucosa tissue.

In some embodiments, the target tissue comprises duodenal mucosa locateddistal to the ampulla of Vater.

In some embodiments, the target tissue comprises at least 10% of theduodenal mucosa located distal to the ampulla of Vater.

In some embodiments, the target tissue comprises at least 15% of theduodenal mucosa located distal to the ampulla of Vater.

In some embodiments, the target tissue comprises at least 25% of theduodenal mucosa located distal to the ampulla of Vater.

In some embodiments, the target tissue comprises at least 15% of theduodenal mucosa located distal to the ampulla of Vater.

In some embodiments, the target tissue comprises at least 50% of theduodenal mucosa located distal to the ampulla of Vater.

In some embodiments, the target tissue comprises an axial length (e.g. acumulative axial length) of duodenal mucosa of at least 6 cm, such as atleast 7 cm, at least 8 cm, at least 9 cm or approximately 9.3 cm ofduodenal mucosa. The cumulative axial length can be treated by treating(e.g. ablating) one or more (e.g. three) full or partial circumferentialaxial segments of the duodenum.

In some embodiments, the target tissue does not comprise any duodenalmucosa located proximal to the ampulla of Vater.

In some embodiments, the target tissue comprises no more than 70% of theduodenal mucosa located distal to the ampulla of Vater and the targettissue does not comprise any duodenal mucosa tissue located proximal tothe ampulla of Vater.

In some embodiments, the target tissue comprises no more than 90% of theduodenal mucosa located distal to the ampulla of Vater and the targettissue does not comprise any duodenal mucosa tissue located proximal tothe ampulla of Vater.

In some embodiments, the target tissue comprises tissue located at least1 cm distal to the ampulla of Vater, such as when the target tissue doesnot include tissue within 1 cm of the ampulla of Vater.

In some embodiments, the system further comprises at least onedeployable marker, and the target tissue comprises tissue selected basedon the deployment location of the at least one marker.

In some embodiments, the system is configured to alter the intestinalmucosal hormone production from the region of treated target tissue.

In some embodiments, the system is configured to alter a hormonalsecretion pattern that affects blood glucose levels in the fasting andpost-prandial states.

In some embodiments, the system is configured to change the blood levelsof GIP and/or GLP-1 to change glucose homeostasis in the fasting and/orpost-prandial states.

In some embodiments, the system is configured to change insulin and/orglucagon secretion from the pancreas and/or insulin and/or glucagonlevels in the bloodstream.

In some embodiments, the system is configured to change pancreatic betacell function and/or health through direct hormonal consequences of thetreated duodenal tissue and/or indirectly through improved blood glucoselevels.

In some embodiments, the system is configured to cause a change in apatient secretion parameter. The system can be configured to cause thechange in a patient secretion parameter by causing an effect selectedfrom the group consisting of: modifying the target tissue; ablating,removing and/or causing the necrosis of the target tissue resulting inreplacement of the target tissue with new tissue; reducing the surfacearea of the target tissue; and combinations thereof. The system can beconfigured to modify the target tissue to cause the change in a patientsecretion parameter. The modified target tissue can comprise tissue withdifferent secretion parameters than the pre-treated tissue. The modifiedtarget tissue can comprise tissue with reduced surface area than thepre-treated tissue. The system can be configured to ablate, cause thenecrosis of and/or remove the target tissue, resulting in replacement ofthe target tissue with new tissue, to cause the change in a patientsecretion parameter. The new tissue can comprise tissue with differentsecretion parameters than the pre-treated tissue. The new tissue cancomprise tissue with reduced surface area than the pre-treated tissue.The patient secretion parameter can comprise a secretion parameterselected from the group consisting of: quantity of a patient secretionduring a time period; average rate of a patient secretion during a timeperiod; peak excursion of a patient secretion parameter; andcombinations thereof. The system can be configured to cause a change inmultiple patient secretion parameters. The change in a patient secretionparameter can be exhibited when the patient is in a state selected fromthe group consisting of: fasting state; post-prandial state; andcombinations thereof. The change in a patient secretion parameter cancomprise at least a 10% reduction in GIP secretions. The at least a 10%reduction in GIP secretions can comprise at least a 10% reduction in theamount of GIP secreted in a time period. The at least a 10% reduction inGIP secretions can comprise at least a 10% reduction in the average rateof GIP secretions during a time period. The at least a 10% reduction inGIP secretions can comprise at least a 25% reduction in GIP secretions.The at least a 10% reduction in GIP secretions can comprise at least a50% reduction in GIP secretions. The change in a patient secretionparameter can result in a reduction in GIP serum concentration selectedfrom the group consisting of: reduced 10%; reduced 25%; and/or reduced50%. The change in a patient secretion parameter can comprise at least a10% increase in GLP-1 secretions. The at least a 10% increase in GLP-1secretions can comprise at least a 10% increase in the amount of GLP-1secreted in a time period. The at least a 10% increase in GLP-1secretions can comprise at least a 10% increase in the average rate ofGLP-1 secretions during a time period. The at least a 10% increase inGLP-1 secretions can comprise at least a 25% increase in GLP-1secretions. The at least a 10% increase in GLP-1 secretions can compriseat least a 50% increase in GLP-1 secretions. The change in a patientsecretion parameter can result in an increase in GLP-1 serumconcentration selected from the group consisting of: increased 10%;increased 25%; and/or increased 50%. The change in a patient secretionparameter can comprise at least a 10% reduction in glucagon secretions.The at least a 10% reduction in glucagon secretions can comprise atleast a 10% reduction in the amount of glucagon secreted in a timeperiod. The at least a 10% reduction in glucagon secretions can compriseat least a 10% reduction in the average rate of glucagon secretionsduring a time period. The at least a 10% reduction in glucagonsecretions can comprise at least a 25% reduction in glucagon secretions.The at least a 10% reduction in glucagon secretions can comprise atleast a 50% reduction in glucagon secretions. The change in a patientsecretion parameter can result in a reduction in glucagon serumconcentration selected from the group consisting of: reduced 10%;reduced 25%; and reduced 50%.

In some embodiments, the system is configured to cause a change in apatient absorption parameter. The system can be configured to cause thechange in a patient absorption parameter by causing an effect selectedfrom the group consisting of: modifying the target tissue; ablating,removing and/or causing the necrosis of target tissue resulting inreplacement of the target tissue with new tissue; reducing the surfacearea of the target tissue; and combinations thereof. The system can beconfigured to modify the target tissue to cause the change in a patientabsorption parameter. The modified target tissue can comprise tissuewith different absorption parameters than the pre-treated tissue. Themodified target tissue can comprise tissue with reduced surface areathan the pre-treated tissue. The system can be configured to ablate,cause the necrosis of and/or remove the target tissue, resulting inreplacement of the target tissue with new tissue, to cause the change ina patient absorption parameter. The new tissue can comprise tissue withdifferent absorption parameters than the pre-treated tissue. The newtissue can comprise tissue with reduced surface area than thepre-treated tissue. The patient absorption parameter can comprise anabsorption parameter selected from the group consisting of: quantity ofa substance absorbed during a time period; average rate of a substanceabsorbed during a time period; and combinations thereof. The system canbe configured to cause a change in multiple patient absorptionparameters. The change in a patient absorption parameter can beexhibited when the patient is in a state selected from the groupconsisting of: fasting state; post-prandial state; and combinationsthereof. The change in a patient absorption parameter can comprise atleast a 10% decrease in glucose absorption. The at least a 10% decreasein glucose absorption can comprise at least a 10% decrease in the amountof glucose absorbed in a time period. The at least a 10% decrease inglucose absorption can comprise at least a 10% decrease in the averagerate of glucose absorption during a time period. The at least a 10%decrease in glucose absorption can comprise at least a 25% decrease inglucose absorption. The at least a 10% decrease in glucose absorptioncan comprise at least a 50% decrease in glucose absorption.

In some embodiments, the system is configured to cause a decrease in GIPand an increase in GLP-1.

In some embodiments, a pre-treatment GIP/GLP-1 ratio comprises the ratioof GIP secretion levels prior to the treatment of the target tissuecompared to the GLP-1 secretion levels prior to the treatment of thetarget tissue, and a post-treatment GIP/GLP-1 ratio comprises the ratioof GIP secretion levels after the treatment of the target tissuecompared to the GLP-1 secretion levels after the treatment of the targettissue. A treatment effect comprises the ratio of the post-treatmentGIP/GLP-1 ratio compared to the pre-treatment GIP/GLP-1 ratio and thesystem can be configured to cause a treatment effect of less than 1.0.The system can be configured to cause a treatment effect of less than0.90. The system can be configured to cause a treatment effect of lessthan 0.75. The system can be configured to cause a treatment effect ofless than 0.50.

In some embodiments, the tissue treatment device further comprises atissue expanding element.

In some embodiments, the tissue treatment element comprises an elementselected from the group consisting of: an ablative fluid delivered to aballoon or other expandable fluid reservoir; a tissue treatment elementcomprising an energy delivery element mounted to an expandable assemblysuch as an electrode or other energy delivery element configured todeliver radiofrequency (RF) energy and/or microwave energy; a lightdelivery element configured to deliver laser or other light energy; afluid delivery element configured to deliver ablative fluid directlyonto tissue; a sound delivery element such as a ultrasonic and/orsubsonic sound delivery element; and combinations thereof.

In some embodiments, the tissue treatment element comprises a firsttissue treatment element and a second tissue treatment element. Thefirst tissue treatment element can be dissimilar to the second tissuetreatment element.

In some embodiments, the tissue treatment device further comprises anexpandable balloon, and the tissue treatment element comprises ablativefluid delivered to the expandable balloon. The ablative fluid cancomprise fluid at sufficiently high temperature to cause tissuenecrosis. The expandable balloon can comprise a material selected fromthe group consisting of: polyethylene terephthalate (PET); nylon; latex;polyurethane; Pebax; and combinations thereof. The expandable ballooncan comprise a wall comprising a thickness between approximately 0.0002″and 0.0020″. The expandable balloon can comprise a wall comprising athickness of approximately 0.0005″. The expandable balloon can comprisea wall comprising a thickness of approximately 0.0010″. The expandableballoon can comprise a tissue contacting portion. The tissue contactingportion can comprise a diameter of between approximately 19.0 mm and32.0 mm. The tissue contacting portion can comprise a length of betweenapproximately 16.0 mm and 35.0 mm. The tissue contacting portion cancomprise a length of between approximately 19.5 mm and 32.9 mm. Thetissue contacting portion can comprise a surface area of betweenapproximately 1750 mm² and 2150 mm². The tissue contacting portion cancomprise a surface area of approximately 1950 mm². The expandableballoon can comprise a tapered distal end. The expandable balloontapered distal end can comprise a taper between approximately 27° and33°. The expandable balloon can comprise a tapered proximal end. Theexpandable balloon tapered proximal end can comprise a taper betweenapproximately 42° and 48°. The expandable balloon can be constructed andarranged to be filled with approximately 10 ml to 35 ml of ablativefluid. The tissue treatment device can comprise a first tissue treatmentdevice, and the system can further comprise a second tissue treatmentdevice comprising a second tissue treatment element and a secondexpandable balloon. The first tissue treatment device expandable ballooncan comprise a first tissue contacting surface area and the secondexpandable balloon can comprise a second tissue contacting surface areasimilar to the first tissue contacting surface area. The first tissuetreatment device expandable balloon can comprise a different lengthand/or diameter than the second expandable balloon of the second tissuetreatment device.

In some embodiments, the system is configured to both cool and heat thetarget tissue. The system can be configured to: in a first step, coolthe target tissue with the tissue treatment element by supplying a firstfluid to the treatment element for a first time period, and the firstfluid is supplied within a first temperature range; in a second step,heat the target tissue with the tissue treatment element by supplying asecond fluid to the treatment element for a second time period, and thesecond fluid is supplied within a second temperature range; and in athird step, cool the target tissue with the tissue treatment element bysupplying a third fluid to the treatment element for a third timeperiod, and the third fluid is supplied within a third temperaturerange. The heating of the target tissue in the second step can beconfigured to ablate the target tissue. The first time period cancomprise a duration (e.g. a time duration) of between approximately 15seconds and 30 seconds. The first temperature range can comprise one ormore temperatures between approximately 5° C. and 25° C., such asbetween 15° C. and 25° C. The second time period can comprise a durationof between approximately 8 seconds and 15 seconds. The first temperaturerange can comprise one or more temperatures between approximately 85° C.and 95° C. The second time period can comprise a duration of betweenapproximately 15 seconds and 30 seconds. The first temperature range cancomprise one or more temperatures between approximately 5° C. and 25°C., such as between 15° C. and 25° C. The second time period cancomprise a duration less than the first time period duration. The secondtime period can comprise a duration less than the third time periodduration. The second time period can comprise a duration less than boththe first time period duration and the third time period duration. Thesecond temperature can comprise a temperature at least 18° above thefirst temperature and/or the third temperature. The second temperaturecan comprise a temperature at least 60° above the first temperatureand/or the third temperature. The first temperature and the thirdtemperature can comprise similar temperatures.

In some embodiments, the tissue treatment device comprises an expandableassembly comprising the tissue treatment element, and the system isconfigured to monitor the pressure and/or volume of the expandableassembly. The system can be configured to use the monitored pressureand/or volume to compensate for peristalsis and/or muscle contractionsof the GI tract. The system can be configured to use the monitoredpressure and/or volume to compensate for changes in GI tract lumendiameter.

In some embodiments, the system is configured expand tissue, and thesystem is further configured to only ablate target tissue comprising:the expanded tissue and/or tissue proximate the expanded tissue.

In some embodiments, the tissue treatment element comprises ablativefluid and the tissue treatment device comprises an expandable balloonconstructed and arranged to receive the ablative fluid. The expandableballoon comprises a tissue contacting portion including a length, andthe system is configured to translate the expandable balloonapproximately the length of the tissue contacting portion after a firstportion of target tissue is treated. The translation can comprise amanual translation (e.g. performed by a clinician). The system canfurther comprise a motion transfer assembly and the translationcomprises at least a semi-automated translation.

In some embodiments, the system is configured to treat a first, secondand third portion of target tissue and to perform an assessment of thedistance between the most proximal tissue treated and non-target tissue.The second target tissue portion can be distal to the third targettissue portion, and the first target tissue portion can be distal to thesecond target tissue portion, and the system can be configured to treatthe first target tissue portion, the second target tissue portion, andthen the third target tissue portion sequentially. The non-target tissuecan comprise the ampulla of Vater, and non-target tissue can includetissue within 1 cm of the ampulla of Vater (e.g. on either side). Thesystem can be configured to treat a fourth portion of target tissueproximal to the most proximal tissue treated, if the distance betweenthe most proximal tissue treated and the non-target tissue is above athreshold.

In some embodiments, the system is configured to prevent two ablationswithin a pre-determined time period. The pre-determined time period canbe configured to prevent repetitive ablations in similar portions of theGI tract.

In some embodiments, the system is configured to prevent a tissueablation and/or tissue treatment until a submucosal expansion step hasbeen performed.

In some embodiments, the system is configured to expand tissue, and thetreatment of the target tissue is completed within 120 minutes ofinitiating tissue expansion. The treatment of the target tissue can becompleted within 60 minutes of initiating tissue expansion. Thetreatment of the target tissue can be completed within 45 minutes ofinitiating tissue expansion.

In some embodiments, the system is configured to select target tissuebased on a patient condition. The amount of target tissue can beproportional to the severity of the patient condition. The amount oftarget tissue can be proportional to the disease burden of the patientcondition. An elevated disease burden can comprise one or more of:relatively long duration since diagnosis; higher HbA1c level than astandard diabetic patient; and more mucosal hypertrophy than a standarddiabetic patient. The amount of target tissue can be proportional to theHbA1c level of the patient.

In some embodiments, the system is configured to provide post-proceduremanagement of the patient after the treatment of the target tissue. Thepost-procedure management can comprise a liquid diet for at least oneday. The post-procedure management can comprise a low sugar diet and/ora low fat diet for at least one week. The post-procedure management cancomprise a standardized diabetic diet for at least 1 week. Thepost-procedure management can comprise nutritional counseling for atleast 1 week.

In some embodiments, the system further comprises a console configuredto interface with at least the tissue treatment device. The console cancomprise a controller. The console can comprise an energy delivery unit.The tissue treatment element can comprise ablative fluid and the energydelivery unit can be constructed and arranged to provide the ablativefluid to the tissue treatment device. The console can comprise a userinterface. The console can comprise a safety-switch. The safety-switchcan be configured to be activated without articulation of an operatordigit of a hand. The tissue treatment device can comprise an expandableassembly, and the system can be configured to automatically contract theexpandable assembly if the safety-switch is not activated. The tissuetreatment device can comprise a balloon, the tissue treatment elementcan comprise ablative fluid, the system can comprise neutralizing fluid,and the system can be configured to automatically replace ablative fluidin the balloon with the neutralizing fluid if the safety switch is notactivated. The tissue treatment device can comprise a balloon, thetissue treatment element can comprise ablative fluid, the system cancomprise cooling fluid, and the system can be configured to deliver theablative fluid to the balloon upon activation of the safety-switch, suchas at a time after which cooling fluid has been delivered to the balloonand an operator has confirmed proper position of the balloon fortreatment of target tissue. The safety-switch can be configured to allowhands-free activation and/or maintenance of a treatment step such thatone or more operators can maintain their hands on one or more of: thetissue treatment device; an endoscope; a tissue expansion device; and alumen diameter sizing device. The safety-switch can comprise a footactivated switch. The safety-switch can comprise a hand-detectionsensor. The tissue treatment device can comprise a handle, and thesafety switch can be constructed and arranged to detect the position ofan operator hand on at least the tissue treatment device handle. Thesystem can comprise an endoscope including a handle, and the safetyswitch can be constructed and arranged to detect the position of anoperator hand on at least the endoscope handle. The console can comprisea pressure assembly. The console can comprise a fluid source. Theconsole can comprise a functional element.

In some embodiments, the system further comprises a functional element.The tissue treatment device can comprise the functional element. Thesystem can further comprise a console and the console can comprise thefunctional element. The system can further comprise a tissue expansiondevice, and the tissue expansion device can comprise the functionalelement. The system can further comprise a gastrointestinal lumen sizingdevice and the sizing device can comprise the function element. Thefunctional element can comprise a sensor selected from the groupconsisting of: temperature sensor such as a thermocouple, thermistor,resistance temperature detector and optical temperature sensor; straingauge; impedance sensor such as a tissue impedance sensor; pressuresensor; blood sensor; optical sensor such as a light sensor; soundsensor such as an ultrasound sensor; electromagnetic sensor such as anelectromagnetic field sensor; visual sensor; and combinations thereof.The functional element can comprise a transducer selected from the groupconsisting of: a heat generating element; a drug delivery element suchas an iontophoretic drug delivery element; a magnetic field generator;an ultrasound wave generator such as a piezo crystal; a light producingelement such as a visible and/or infrared light emitting diode; a motor;a vibrational transducer; a fluid agitating element; and combinationsthereof.

In some embodiments, the system further comprises a tissue expansiondevice including at least one fluid delivery element constructed andarranged to deliver injectate to expand one or more tissue layers. Thesystem can further comprise an injectate, and the injectate is selectedfrom the group consisting of: water; saline; a fluid with a dye such asa visible dye such as indigo carmine; methylene blue; India ink; SPOTdye; a gel; a hydrogel; a protein hydrogel; a fluid containing avisualizable media such as a media visualizable under X-ray, ultrasoundimaging and/or magnetic resonance imaging; ethylene vinyl alcohol(EVOH); and combinations thereof. The tissue expansion device cancomprise an expandable balloon and the at least one fluid deliveryelement can be attached to the balloon. The tissue expansion device canfurther comprise a tissue capture port surround the at least one fluiddelivery element. The system can be configured to deliver a first fluidvolume to the expandable balloon and measure a first pressure and todeliver a second fluid volume to the expandable balloon and measure asecond pressure, such as when the second fluid of volume is less thanthe first fluid volume. The system can be further configured to apply afirst vacuum while the expandable balloon is filled with the secondvolume of fluid, to cause tissue to enter the tissue capture port. Thesystem can be configured to confirm the first pressure is less than thesecond pressure. The tissue expansion device can further comprise anexpandable assembly comprising the at least one fluid delivery element.The expandable assembly can comprise an expandable balloon. The systemcan be configured to measure the pressure and/or volume and to determineif a proper volume of the injectate has been delivered to achieveadequate tissue expansion based on the measured pressure and/or volume.The system can be configured to expand tissue located at least 0.5 cmdistal to the ampulla of Vater, such as when tissue within 0.5 cm distalto the ampulla of Vater is not expanded and/or is not subsequentlyablated. The system can be configured to expand tissue located at least1 cm distal to the ampulla of Vater, such as when tissue within 1 cm ofthe ampulla of Vater is not expanded and/or is not subsequently ablated.The system can be configured to expand tissue located at least 2 cmdistal to the ampulla of Vater, such as when tissue within 2 cm of theampulla of Vater is not expanded and/or is not subsequently ablated. Thesystem can be configured to expand tissue located at least 3 cm distalto the ampulla of Vater, such as when tissue within 3 cm of the ampullaof Vater is not expanded and/or is not subsequently ablated. The systemcan be configured to expand tissue located within 5 cm distal to theampulla of Vater. The system can be configured to expand tissue locatedwithin 10 cm distal to the ampulla of Vater. The at least one fluiddelivery element can comprise at least three fluid delivery elements.The tissue expansion device can further comprise an expandable assembly,and the at least three fluid delivery elements can comprise three fluiddelivery elements positioned with approximately 120° separation on theexpandable assembly. The at least three fluid delivery elements can beconstructed and arranged to create full circumferential expansion of asegment of submucosal tissue of the duodenum. The tissue expansiondevice can be constructed and arranged to deliver at least 1 ml ofinjectate per injection from the at least one fluid delivery element.The tissue expansion device can be constructed and arranged to deliverat least 2 ml of injectate per injection from the at least one fluiddelivery element. The tissue expansion device can be constructed andarranged to deliver at least 5 ml of injectate per injection from the atleast one fluid delivery element. The tissue expansion device can beconstructed and arranged to deliver at least 8 ml of injectate perinjection from the at least one fluid delivery element. The tissueexpansion device can be configured to deliver multiple injections ofinjectate along a length of the GI tract, and the injections can beaxially separated by at least 0.5 cm. The tissue expansion device can beconfigured to deliver the multiple injections of injectate with an axialseparation of at least 1.0 cm. The tissue expansion device can beconfigured to deliver the multiple injections of injectate with an axialseparation of at least 2.0 cm. The tissue expansion device can beconfigured to deliver the multiple injections of injectate with an axialseparation of at least 3.0 cm. The tissue expansion device can beconfigured to deliver the multiple injections of injectate with an axialseparation of at least 4.0 cm. The tissue expansion device can beconfigured to deliver the multiple injections of injectate with an axialseparation of at least 6.0 cm. The at least one fluid delivery elementcan comprise at least two fluid delivery elements (e.g. multiple fluiddelivery elements configured to simultaneously or sequentially deliversets of injections), and the tissue expansion device can be configuredto deliver at least 5 sets of injections at different axial locationsalong the length of the duodenum. The tissue expansion device can beconfigured to deliver at least 8 sets of injections at different axiallocations along the length of the duodenum. The tissue expansion devicecan be configured to deliver between 8 and 12 sets of injections atdifferent axial locations along the length of the duodenum. Each set ofinjections can comprise a first injection from a first fluid deliveryelement and a second injection from a second fluid delivery element,each set of injections delivered along a circumference of a GI tractaxial location. Each set of injections can comprise a first injectionfrom a first fluid delivery element, a second injection from a secondfluid delivery element, and a third injection from a third fluiddelivery element, each set of injections delivered along a circumferenceof a GI tract axial location. The sets of injections can be positionedwith an axial separation of at least 0.5 cm. The sets of injections canbe positioned with an axial separation of between 1.0 cm and 5.0 cm. Thesets of injections can be positioned with an axial separation of between1.0 cm and 2.0 cm. The tissue expansion device can comprise a balloonwith a balloon length and the at least two fluid delivery element aremounted to the balloon, and the sets of injections can be positionedwith an axial separation of approximately one-half the balloon length.The sets of injections can be delivered proximally to distally along theGI tract. The sets of injections can be delivered distally to proximallyalong the GI tract.

In some embodiments, the system further comprises a lumen diametersizing device constructed and arranged to provide GI lumen diameterinformation. The lumen diameter sizing device can comprise an expandableballoon. The system can be configured to determine the volume deliveredto the lumen diameter sizing device expandable balloon. The system canbe configured to deliver fluid to the lumen diameter sizing deviceexpandable balloon until a threshold pressure is achieved. The thresholdpressure can comprise a threshold of at least 0.7 psi. The lumendiameter sizing device can be configured to determine the luminaldiameter of at least two GI tract axial locations. The system can beconfigured to determine the size of the tissue treatment device to beused based on the GI lumen diameter information provided by the lumendiameter sizing device. The system can further comprise a tissueexpansion device and the system can be configured to determine the sizeof the tissue expansion device to be used based on the GI lumen diameterinformation provided by the lumen diameter sizing device.

In some embodiments, the system further comprises an agent. The agentcan be configured to be delivered to the GI tract. The agent can beconfigured to be delivered systemically to the patient. The agent cancomprise an anti-peristaltic agent. The agent can comprise L-menthol.The agent can comprise an agent selected from the group consisting of:glucagon; buscopan; and combinations thereof.

In some embodiments, the system further comprises a marker constructedand arranged to be deployed within the patient. The marker can beconstructed and arranged to identify a location relative to non-targettissue. The non-target tissue can comprise the ampulla of Vater, and itcan include tissue proximate the ampulla of Vater, such as tissue within1 cm, 2 cm or 3 cm of the ampulla of Vater. The marker can comprise anelement selected from the group consisting of: a visible marker; aradiographic marker; an ultrasonically reflectable marker; ink; dye; andcombinations thereof. The marker can comprise multiple markers. Thesystem can further comprise an endoscope and the marker can beconstructed and arranged to be deployed by the endoscope. The marker canbe constructed and arranged to be deployed by the tissue treatmentdevice.

In some embodiments, the system further comprises an endoscope and ascope attached sheath attachable to the endoscope. The tissue treatmentdevice can be constructed and arranged to be inserted through the scopeattached sheath.

According to another aspect of the present inventive concepts, a tissuetreatment device for treating target tissue comprises a tissue treatmentelement constructed and arranged to apply a tissue modifying agent totarget tissue and the system is constructed and arranged to provide atherapeutic benefit to the patient.

In some embodiments, the target tissue comprises duodenal mucosa.

In some embodiments, the tissue treatment element comprises anexpandable element. The tissue treatment element can expand whencontacted with fluid. The tissue treatment element can expand whencontacted with the tissue modifying agent.

In some embodiments, the tissue treatment element comprises a spongematerial. The sponge material can be selected from the group consistingof: a sponge material such as a natural sponge material or a syntheticsponge material; a foamed polyurethane; a polyvinyl alcohol (PVA)sponge; a hydrogel; a super-absorbent polymer; and combinations thereof.

In some embodiments, the tissue treatment element comprises a balloon.The balloon can comprise a permeable balloon.

In some embodiments, the tissue treatment device further comprises thetissue modifying agent.

In some embodiments, the tissue modifying agent is configured to causenecrosis of the target tissue. The tissue modifying agent can beselected from the group consisting of: a chemical peeling agent; a mildacid such as glycolic acid; trichloroacetic acid; a mild base; phenol;retinoic acid; and combinations thereof.

In some embodiments, the tissue treatment device further comprises ashaft with a proximal end and a distal portion, and the tissue treatmentelement is positioned on the distal portion of the shaft. The shaft cancomprise a length sufficient to position the tissue treatment elementproximate the distal end of the duodenum of the patient. The shaft cancomprise a lumen constructed and arranged for over-the-wire insertion ofthe tissue treatment device. The tissue treatment device can furthercomprise a handle positioned on the proximal end of the shaft.

In some embodiments, the tissue treatment device further comprises atleast one occluding element constructed and arranged to at leastpartially occlude a lumen of the GI tract. The at least one occludingelement can be further configured to prevent migration of the tissuemodifying agent to non-target tissue. The at least one occluding elementcan comprise a radially expandable element. The at least one occludingelement can comprise an expandable balloon. The at least one occludingelement can comprise an expandable sponge. The at least one occludingelement can comprise multiple occluding elements. The at least oneoccluding element can be constructed and arranged to be evacuated fromthe patient by the patient's digestive system. The tissue treatmentdevice can further comprise a grasping device, and the at least oneoccluding element can be constructed and arranged to be removed from thepatient by the grasping device. The tissue treatment device can furthercomprise a shaft with a lumen, and the at least one occluding elementcan be constructed and arranged to be deployed into the patient via theshaft lumen. The tissue treatment device can further comprise a push rodtranslatable through the lumen and constructed and arranged to expel theoccluding element from the shaft.

According to another aspect of the present inventive concepts, a tissuemodifying agent delivery system comprises a tissue treatment device asdescribed herein. The system further comprises a tissue modifying agentdelivery unit configured to deliver a tissue modifying agent to thetissue treatment element.

In some embodiments, the tissue modifying agent delivery systemcomprises a system as described herein.

In some embodiments, the target tissue comprises duodenal mucosa locateddistal to the ampulla of Vater. The target tissue can comprise tissue atleast 0.5 cm distal to the ampulla of Vater, such as when tissue within0.5 cm of the ampulla of Vater is not ablated or otherwise treated. Thetarget tissue can comprise tissue at least 1 cm distal to the ampulla ofVater, such as when tissue within 1 cm of the ampulla of Vater is notablated or otherwise treated. The target tissue comprises tissue atleast 2 cm distal to the ampulla of Vater, such as when tissue within 2cm of the ampulla of Vater is not ablated or otherwise treated. Thetarget tissue comprises tissue at least 3 cm distal to the ampulla ofVater, such as when tissue within 3 cm of the ampulla of Vater is notablated or otherwise treated.

In some embodiments, the target tissue comprises at least 25% of theduodenal mucosa located distal to the ampulla of Vater.

In some embodiments, the target tissue comprises at least 50% of theduodenal mucosa located distal to the ampulla of Vater.

In some embodiments, the target tissue does not comprise any duodenalmucosa located proximal to the ampulla of Vater.

In some embodiments, the target tissue comprises no more than 75% of theduodenal mucosa located distal to the ampulla of Vater and the targettissue does not comprise any duodenal mucosa tissue located proximal tothe ampulla of Vater.

In some embodiments, the target tissue comprises no more than 90% of theduodenal mucosa located distal to the ampulla of Vater and the targettissue does not comprise any duodenal mucosa tissue located proximal tothe ampulla of Vater.

In some embodiments, the target tissue comprises tissue located at least1 cm distal to the ampulla of Vater.

In some embodiments, the system further comprises at least onedeployable marker, and the target tissue comprises tissue selected basedon the deployment location of the at least one marker.

In some embodiments, the target tissue comprises an axial length of atleast 6 cm. The target tissue can comprise an axial length of at least 9cm.

In some embodiments, the target tissue comprises a single contiguoussegment of duodenal mucosa.

In some embodiments, the target tissue comprises multiple discontiguoussegments of duodenal mucosa.

In some embodiments, the target tissue comprises tissue at least 1 cmdistal to the ampulla of Vater, such as when tissue within 1 cm of theampulla of Vater is not ablated or otherwise treated. The target tissuecan comprise tissue at least 2 cm distal to the ampulla of Vater, suchas when tissue within 2 cm of the ampulla of Vater is not ablated orotherwise treated. The target tissue can comprise tissue at least 3 cmdistal to the ampulla of Vater, such as when tissue within 3 cm of theampulla of Vater is not ablated or otherwise treated.

In some embodiments, the system of the present inventive conceptscomprises a first tissue treatment device and a second tissue treatmentdevice, each tissue treatment device comprising a tissue treatmentelement constructed and arranged to treat (e.g. ablate, remove orotherwise modify) target tissue. The first tissue treatment device isconstructed and arranged to treat duodenal mucosa in a first procedure,and the second tissue treatment device is constructed and arranged totreat duodenal mucosa in a second procedure, such as a second procedureperformed at least one week after the first procedure. The target tissuecan comprise at least duodenal mucosa tissue, such as to treat diabetesof a patient.

According to another aspect of the present inventive concepts, a methodof treating tissue is performed using any of the systems and/or devicesdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of embodimentsof the present inventive concepts will be apparent from the moreparticular description of preferred embodiments, as illustrated in theaccompanying drawings in which like reference characters refer to thesame or like elements. The drawings are not necessarily to scale,emphasis instead being placed upon illustrating the principles of thepreferred embodiments.

FIG. 1 is a schematic view of a system for treating target tissue of apatient, consistent with the present inventive concepts.

FIG. 2 is a flow chart of a method for treating target tissue of apatient, consistent with the present inventive concepts.

FIG. 3 is a side sectional view of the distal portion of a tissuetreatment device inserted into a curvilinear section of duodenum,consistent with the present inventive concepts.

FIGS. 4A, 4B and 4C are perspective, side and end views, respectively,of an expandable element comprising a balloon, consistent with thepresent inventive concepts.

FIG. 5 is a side sectional view of the distal portion of a tissuetreatment device including an agent dispensing element, consistent withthe present inventive concepts

FIGS. 5A-5E are side sectional views of a series of steps for treating asurface of gastrointestinal tissue using the tissue treatment device ofFIG. 5, consistent with the present inventive concepts.

FIG. 6 is a schematic view of a system for treating target tissue of apatient, consistent with the present inventive concepts.

FIG. 7 is a chart showing the number of patients receiving numbers oftreatments.

FIG. 8 is a table of cumulative demographic information.

FIG. 9 is a table showing results of applicant's studies.

FIG. 10 is a graph illustrating HbA1c reductions in patients receivingthree or more ablations.

FIG. 11 is a graph illustrating reduction in FPG levels.

FIG. 12 is a graph illustrating improvement in 2hPG measurements.

FIG. 13 is a graph showing treatment response rates.

FIG. 14 is a graph of HbA1c percentages measured for at least 120 dayspost treatment.

FIG. 15 is a graph of fasting insulin change data over a 3 month period.

FIG. 16 is a graph of SF-36 mental value changes.

FIG. 17 is a graph of weight change in study patients.

FIG. 18 is a graph regarding weight loss and HbA1c.

FIG. 19 is a graph of HbA1c percentages over a six week period comparingresponders and non-responders.

FIG. 20 is a graph of fasting glucose change over a twenty-six weekperiod comparing responders and non-responders.

FIG. 21 is a graph of change under the curve of a mixed meal tolerancetest.

FIG. 22 is a graph of three patients exhibiting a large treatmenteffect.

FIG. 23 is a table presenting the large effect size of high dose cohort.

FIG. 24 is a graph showing the average HbA1c in all available subjectstreated by the systems, devices and methods of the present inventiveconcepts.

FIG. 25 is a graph showing the average change in HbA1C from baseline inpatients with LS-DMR and SS-DMR.

FIGS. 26A and 26B are graphs showing the average fasting plasma glucosein LS-DMR patients with a baseline HbA1C between 7.5% and 10%.

FIG. 27 is a graph showing mean HbA1C in LS-DMR patients with baselineHbA1c between 7.5% and 10% and consistent antidiabetic medications.

FIG. 28 is a graph showing HbA1c over time in a single patient receivingtwo treatments at different intervals.

DETAILED DESCRIPTION OF THE DRAWINGS

The terminology used herein is for the purpose of describing particularembodiments and is not intended to be limiting of the inventiveconcepts. Furthermore, embodiments of the present inventive concepts mayinclude several novel features, no single one of which is solelyresponsible for its desirable attributes or which is essential topracticing an inventive concept described herein. As used herein, thesingular forms “a,” “an” and “the” are intended to include the pluralforms as well, unless the context clearly indicates otherwise.

It will be further understood that the words “comprising” (and any formof comprising, such as “comprise” and “comprises”), “having” (and anyform of having, such as “have” and “has”), “including” (and any form ofincluding, such as “includes” and “include”) or “containing” (and anyform of containing, such as “contains” and “contain”) when used herein,specify the presence of stated features, integers, steps, operations,elements, and/or components, but do not preclude the presence oraddition of one or more other features, integers, steps, operations,elements, components, and/or groups thereof.

It will be understood that, although the terms first, second, third etc.may be used herein to describe various limitations, elements,components, regions, layers and/or sections, these limitations,elements, components, regions, layers and/or sections should not belimited by these terms. These terms are only used to distinguish onelimitation, element, component, region, layer or section from anotherlimitation, element, component, region, layer or section. Thus, a firstlimitation, element, component, region, layer or section discussed belowcould be termed a second limitation, element, component, region, layeror section without departing from the teachings of the presentapplication.

It will be further understood that when an element is referred to asbeing “on”, “attached”, “connected” or “coupled” to another element, itcan be directly on or above, or connected or coupled to, the otherelement, or one or more intervening elements can be present. Incontrast, when an element is referred to as being “directly on”,“directly attached”, “directly connected” or “directly coupled” toanother element, there are no intervening elements present. Other wordsused to describe the relationship between elements should be interpretedin a like fashion (e.g., “between” versus “directly between,” “adjacent”versus “directly adjacent,” etc.).

Spatially relative terms, such as “beneath,” “below,” “lower,” “above,”“upper” and the like may be used to describe an element and/or feature'srelationship to another element(s) and/or feature(s) as, for example,illustrated in the figures. It will be understood that the spatiallyrelative terms are intended to encompass different orientations of thedevice in use and/or operation in addition to the orientation depictedin the figures. For example, if the device in a figure is turned over,elements described as “below” and/or “beneath” other elements orfeatures would then be oriented “above” the other elements or features.The device can be otherwise oriented (e.g., rotated 90 degrees or atother orientations) and the spatially relative descriptors used hereininterpreted accordingly.

The term “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. For example “A and/or B” is to be taken as specificdisclosure of each of (i) A, (ii) B and (iii) A and B, just as if eachis set out individually herein.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination. For example, it will be appreciated thatall features set out in any of the claims (whether independent ordependent) can be combined in any given way.

As described herein, “room pressure” shall mean pressure of theenvironment surrounding the systems and devices of the present inventiveconcepts. Positive pressure includes pressure above room pressure orsimply a pressure that is greater than another pressure, such as apositive differential pressure across a fluid pathway component such asa valve. Negative pressure includes pressure below room pressure or apressure that is less than another pressure, such as a negativedifferential pressure across a fluid component pathway such as a valve.Negative pressure can include a vacuum but does not imply a pressurebelow a vacuum. As used herein, the term “vacuum” can be used to referto a full or partial vacuum, or any negative pressure as describedhereabove. As used herein, the term “vacuum level” refers to a measureof a vacuum wherein the lower the pressure, the greater the vacuumlevel.

The term “diameter” where used herein to describe a non-circulargeometry is to be taken as the diameter of a hypothetical circleapproximating the geometry being described. For example, when describinga cross section, such as the cross section of a component, the term“diameter” shall be taken to represent the diameter of a hypotheticalcircle with the same cross sectional area as the cross section of thecomponent being described.

As used herein, the term “ablative fluid” refers to one or more liquids,gases, gels or other fluids whose thermal properties (at sufficientlyhigh or low temperatures) cause tissue necrosis and/or another desiredtissue modification. Alternatively or additionally, “ablative fluid”refers to one or more fluids whose chemical properties (at roomtemperature, body temperature or otherwise) cause tissue necrosis oranother desired tissue treatment. The tissue treatment element of thepresent inventive concepts can comprise one or more ablative fluids.

It is an object of the present inventive concepts to provide systems,methods and devices for safely and effectively treating a volume oftissue (the “target tissue”), such as to treat a patient disease ordisorder. Target tissue can comprise one or more target tissue segmentsor other target tissue portions. The target tissue can comprise one ormore layers of a portion of tubular or non-tubular tissue, such astissue of an organ or tissue of the gastrointestinal (GI) tract of apatient. The systems and devices of the present inventive concepts caninclude one or more treatment assemblies and/or treatment elementsconfigured to treat target tissue, such as a treatment elementcomprising fluid at an ablative temperature delivered to a balloon(ablative temperature fluid and/or balloon filled with ablative fluideach referred to singly or collectively as a “treatment element” of thepresent inventive concepts). One or more treatment elements can beprovided in, on and/or within an expandable treatment assembly or otherradially deployable mechanism. The treatment assemblies and/or treatmentelements are configured to treat target tissue (e.g. deliver energy totarget tissue), such as to modify target tissue (e.g. to modify thesecretions from the target tissue and/or absorption of the targettissue), ablate target tissue (e.g. to cause the replacement of thetarget tissue with “new tissue”) and/or to cause a reduction in thesurface area of target tissue (e.g. the luminal surface area of an innerwall of tubular tissue) at or proximate to one or more locations wherethe treatment was performed (e.g. proximate the location where energywas delivered). The luminal or other tissue treatment can occur acutelyand/or it can take place over time such as days, weeks or months. Atissue surface area reduction can correspond to a reduction in mucosalsurface area available to function in an absorptive and/or a secretorycapacity. A target tissue treatment can result in the replacement oftarget tissue with new tissue with different absorptive and/or secretorycapacity and/or other desirable effect related to replacement and/ormodification of target tissue. The treatment of target tissue with thesystems, devices and methods of the present inventive concepts canprovide a therapeutic benefit to the patient, such as to treat one ormore diseases or disorders of the patient, as described in detailherebelow.

Each treatment assembly can comprise at least one tissue treatmentelement such as a tissue treatment element selected from the groupconsisting of: an ablative fluid delivered to a balloon or otherexpandable fluid reservoir; an energy delivery element mounted to anexpandable assembly such as an electrode or other energy deliveryelement configured to deliver radiofrequency (RF) energy and/ormicrowave energy; a light delivery element configured to deliver laseror other light energy; a fluid delivery element configured to deliverablative fluid directly onto tissue; a sound delivery element such as aultrasonic and/or subsonic sound delivery element; and combinations ofthese. Numerous forms of treatment assemblies and/or treatment elementscan be included. In some embodiments, the treatment assemblies and/orthe one or more treatment elements contained therein are configured asdescribed in: applicant's co-pending U.S. patent application Ser. No.13/945,138, entitled “Devices and Methods for the Treatment of Tissue”,filed Jul. 18, 2013; applicant's co-pending U.S. patent application Ser.No. 14/470,503, entitled “Heat Ablation Systems, Devices and Methods forthe Treatment of Tissue”, filed Aug. 27, 2014; applicant's co-pendingU.S. patent application Ser. No. 14/609,332, entitled “Electrical EnergyAblation Systems, Devices and Methods for the Treatment of Tissue”,filed Jan. 29, 2015; and/or applicant's co-pending U.S. patentapplication Ser. No. 14/609,334, entitled “Ablation Systems, Devices andMethods for the Treatment of Tissue”, filed Jan. 29, 2015; the contentsof each of which is incorporated herein by reference in its entirety.

The treatment assemblies and/or treatment elements of the presentinventive concepts can deliver treatment (e.g. deliver energy, deliver achemically ablative fluid, mechanically abrade and/or otherwise treattissue) to a particular area of tissue, the “delivery zone”. During asingle delivery of treatment, a treatment element can be constructed andarranged to deliver treatment to a relatively continuous surface oftissue (e.g. a continuous surface of tissue in contact with a balloonfilled with ablative fluid or a surface of tissue onto which achemically ablative fluid is sprayed, coated or otherwise delivered). Inthese continuous-surface treatment delivery embodiments, the deliveryzone comprises the continuous surface of tissue receiving the treatmentdirectly. Alternatively, a treatment element can be constructed andarranged to deliver treatment to multiple discrete portions of a tissuesurface, with one or more tissue surface portions in-between othersurface portions that do not receive energy or other treatment from thetreatment element. In these segmented-surface treatment deliveryembodiments, the delivery zone is defined by a periphery of the multipletissue surface area portions receiving treatment, similar to a “convexhull” or “convex envelope” used in mathematics to define an areaincluding a number of discrete locations that define a periphery. Adelivery zone can comprise two or more contiguous or non-contiguousdelivery zones, and multiple delivery zones can be treated sequentiallyand/or simultaneously.

For example, in embodiments where the treatment element is hot fluid(e.g. ablative fluid at a sufficiently high temperature to cause tissuenecrosis) positioned within a balloon, the delivery zone comprises alltissue surfaces contacted by the balloon that directly receive ablativethermal energy from the ablative fluid through the balloon. Inembodiments, where the treatment element is a balloon filled with coldfluid (e.g. ablative fluid at a sufficiently low temperature to causetissue necrosis), the delivery zone can comprise all tissue surfacescontacted by the balloon that have heat extracted from them by the coldfluid (e.g. at a sufficient cold temperature to treat the tissue). Inembodiments where the treatment element is an array of electrodesconfigured to deliver electrical energy (e.g. RF energy) to tissue, thedelivery zone can comprise an area defined by the electrodes on theperiphery of the array (e.g. a convex hull as described above), such aswhen the electrodes are positioned and energy is delivered to treatrelatively the entire surface of tissue within the periphery. Inembodiments where the treatment element comprises one or more fluiddelivery elements delivering ablative fluid directly to tissue (e.g. anablative fluid whose chemical nature modifies tissue, at bodytemperature or otherwise), the delivery zone can comprise a surfacedefined by the periphery of tissue locations receiving the ablativefluid, such as when the ablative fluid is delivered (e.g. sprayed orotherwise applied, such as via a sponge) to relatively the entiresurface within the periphery. In embodiments where the treatment elementcomprises one or more light delivery elements such as those that deliverlaser energy to tissue, the delivery zone can comprise a surface areadefined by the periphery of tissue locations receiving the light energy,such as when light is delivered at a set of locations and with amagnitude of energy configured to treat relatively the entire surface oftissue within the periphery. In these embodiments, light can bedelivered to relatively the entire energy delivery zone, or to a largenumber (e.g. greater than 100) of tissue locations within the peripheryof the delivery zone (e.g. making up less than 50%, less than 20% orless than 10% of the total surface area of the delivery zone). Inembodiments where the treatment element comprises one or more sounddelivery elements such as those that deliver sub-sonic and/or ultrasonicsound energy to tissue, the delivery zone can comprise a surface areadefined by the periphery of tissue locations receiving the sound energy,such as when ablative sound energy is delivered at a set of locationsand with a magnitude of energy configured to treat relatively the entiresurface of tissue within the periphery. In embodiments in which thetreatment element comprises a mechanical cutter or other abrasionelement, the delivery zone can comprise a surface defined by all tissuedissected, cut, mechanically disrupted and/or otherwise modified duringa single abrading step of the mechanical abrader.

A delivery zone can comprise a cumulative set of delivery zones thatreceive treatment simultaneously or sequentially, by one or more tissuetreatment elements, such as those described immediately hereabove. Adelivery zone can comprise a first delivery zone defined when atreatment element treats target tissue in a first treatment delivery,plus a second delivery zone defined when the treatment element treatstarget tissue in a second treatment delivery, and so on. In theseembodiments, the treatment element can be translated, rotated and/orotherwise repositioned between treatment deliveries, where each deliveryzone is associated with the position of the treatment element duringeach treatment delivery. Multiple delivery zones can receive treatmentin a single procedure, such as within a period of less than twenty-fourhours. A delivery zone can comprise a set of multiple delivery zonestreated by two or more treatment elements.

Target tissue treated by each energy delivery and/or other treatmentdelivery comprises the tissue directly receiving treatment (i.e. thetissue defined by the delivery zone) plus “neighboring tissue” which isalso modified by the associated treatment delivery. The neighboringtissue can comprise tissue alongside, below and/or otherwise proximatethe delivery zone tissue. The neighboring tissue treatment can be due toone or more of: conduction or convection of heat or cold from thedelivery zone; flow of ablative fluid from the delivery zone; flow oftoxins or other agents that occur during cell degradation and/or death;radiation; luminescence, light dissipation; and other energy and/orchemical propagation mechanisms. In some embodiments, an area (i.e. thedelivery zone) comprising an inner surface of mucosal tissue directlyreceives treatment from one or more treatment elements (e.g. an ablativefluid contained within a balloon), and the total volume of target tissuetreated by that single treatment delivery includes: the delivery zonetissue (i.e. surface mucosal tissue directly receiving energy and/orother treatment from the treatment element); surface mucosal tissue inclose proximity (e.g. adjacent) to the delivery zone tissue; and mucosaland potentially submucosal tissue layers beneath (deeper than) thedelivery zone tissue and the treated adjacent surface mucosal tissue.

In some embodiments, a “treatment neutralizing” procedure is performedafter one or more treatment deliveries, such as a treatment neutralizingcooling procedure performed after one or more treatment elements deliveror otherwise generate heat to treat target tissue, or a treatmentneutralizing warming procedure performed after one or more treatmentelements deliver cryogenic energy to treat target tissue. In theseembodiments, the treatment neutralizing cooling or warming fluid can bedelivered to the same expandable assembly (e.g. an expandable assemblycomprising a balloon) delivering the heat or cryogenic treatment,respectively, and/or the neutralizing fluid can be delivered directly totissue. In some embodiments, a treatment element delivers an ablatingagent to target tissue (e.g. a chemical or other agent configured tocause target tissue necrosis or otherwise treat target tissue), and atreatment neutralizing procedure comprises delivery of a neutralizingagent to target and/or non-target tissue to reduce continued ablationdue to the delivered caustic ablative fluid (e.g. a base to neutralize adelivered acid or an acid to neutralize a delivered base).

Each treatment assembly and/or treatment element of the presentinventive concepts can be configured to treat target tissue in one ormore locations of the patient, such as one or more contiguous ordiscontiguous tissue locations. The target tissue comprises a threedimensional volume of tissue, and can include a first portion, atreatment portion, whose treatment has a therapeutic benefit to apatient; as well as a second portion, a “safety-margin” portion, whosetreatment has minimal or no adverse effects to the patient. “Non-targettissue” can be identified (e.g. prior to and/or during the medicalprocedure), wherein the non-target tissue comprises tissue whosetreatment by the treatment assembly and/or treatment element should bereduced or avoided such as to reduce or prevent an undesired effect tothe patient.

The target tissue treatment can cause one or more modifications of thetarget tissue such as a modification selected from the group consistingof: modification of cellular function; cell death; apoptosis; instantcell death; cell necrosis; denaturing of cells; removal of cells; andcombinations of these. In some embodiments, the target tissue treatmentis configured to create scar tissue. Target tissue can be selected suchthat after treatment the treated target tissue and/or the tissue thatreplaces the target tissue functions differently than the pre-treatedtarget tissue, such as to have a therapeutic benefit. The modifiedand/or replacement tissue can have different secretions and/orquantities of secretions than the pre-treated target tissue, such as totreat diabetes, hypercholesterolemia and/or another patient disease ordisorder. The modified and/or replacement tissue can have differentabsorptive properties than the target tissue, such as to treat diabetes,insulin resistance, hypercholesterolemia and/or another patient diseaseor disorder. The modified and/or replacement tissue can have a differentsurface topography than the target tissue, such as a modification of thetopography of the inner wall of the GI tract that includes a smoothingor flattening of its inner surface, such as a modification in which theluminal surface area of one or more segments of the GI tract (e.g. oneor more duodenal segments) is reduced after treatment. The effect of thetreatment can occur acutely, such as within twenty-four hours, or afterlonger periods of time such as greater than twenty-four hours or greaterthan one week.

Target tissue to be treated can comprise two or more discrete tissuesegments, such as two or more axial segments of the GI tract. Eachtissue segment can comprise a full or partial circumferential segment ofthe tissue segment. Multiple tissue segments can be treated with thesame or different treatment elements, and they can be treatedsimultaneously or in sequential steps (e.g. sequential energy deliverysteps that deliver energy to multiple delivery zones). Multiple tissuesegments can be treated in the same or different clinical procedures(e.g. procedures performed on different days). In some embodiments, aseries of tissue segments comprising a series of axial segments of theGI tract (e.g. a series of axial segments of the duodenum) are treatedin a single clinical procedure. The first and second tissue segments canbe directly adjacent, they can contain overlapping portions of tissue,and there can be gaps between the segments. Dissimilarities in treatmentelements can include type and/or amount of energy to be delivered by anenergy delivery based treatment element. Dissimilarities in targettissue treatments can include: target tissue area treated; target tissuevolume treated; target tissue length treated; target tissue depthtreated; target tissue circumferential portion treated; ablative fluidtype, volume and/or temperature delivered to a treatment elementcomprising a reservoir such as a balloon; ablative fluid type, volumeand/or temperature delivered directly to tissue; energy delivery type;energy delivery rate and/or amount; peak energy delivered; averagetemperature of target tissue achieved during target tissue treatment;maximum temperature achieved during target tissue treatment; temperatureprofile of target tissue treatment; duration of target tissue treatment;surface area reduction achieved by target tissue treatment; andcombinations of these.

Target tissue can include tissue of the duodenum, such as tissueincluding substantially all or a portion of the mucosal layer of one ormore axial segments of the duodenum (e.g. including all or a portion ofthe plicae circulares), such as to treat diabetes, hypercholesterolemiaand/or another patient disease or disorder, such as while leaving theduodenum anatomically connected after treatment. Target tissue caninclude one or more portions of a tissue layer selected from the groupconsisting of: mucosa; mucosa through superficial submucosa; mucosathrough mid-submucosa; mucosa through deep-submucosa; and combinationsof these. Replacement tissue can comprise cells that have migrated fromone or more of: gastric mucosa; jejunal mucosa; an untreated portion ofthe duodenum whose mucosal tissue functions differently than the treatedmucosal tissue functions prior to treatment; and combinations of these.Replacement tissue can include one or more tissue types selected fromthe group consisting of: scar tissue; normal intestinal mucosa; gastricmucosa; and combinations of these. In some embodiments, target tissueincludes a treatment portion comprising the mucosal layer of theduodenum, and a safety-margin portion comprising a near-full-depth orpartial-depth layer of the submucosal layer of the duodenum. In someembodiments, the target tissue comprises nearly the entire mucosal layerof the duodenum, and can include a portion of the pylorus contiguouswith the duodenal mucosa and/or a portion of the jejunum contiguous withthe duodenal mucosa. In some embodiments, the target tissue comprisesall or a portion of the duodenal mucosa distal to the ampulla of Vater,such as when tissue within 0.5 cm or within 1 cm of the ampulla of Vateris not ablated or otherwise treated. In these embodiments, the targettissue can comprise at least 10%, at least 15%, at least 25%, at least30% or at least 50% of the duodenal mucosa distal to the ampulla ofVater. Alternatively or additionally, the target tissue can comprise nomore than 70% or no more than 90% of the duodenal mucosa distal to theampulla of Vater. In these embodiments, tissue proximal to and/orproximate the ampulla of Vater can comprise non-target tissue (i.e.tissue whose treatment is avoided or at least reduced).

In some embodiments, the target tissue comprises at least a portion ofduodenal mucosal tissue, and the systems, methods and devices of thepresent inventive concepts are configured to counteract duodenal mucosalchanges that cause an intestinal hormonal impairment leading to insulinresistance in patients. In these embodiments, the therapy provided canimprove the body's ability to process sugar and dramatically improveglycemic control for patients with insulin resistance and/or Type 2diabetes.

Hormones released from the intestinal mucosa play an important role inmodulating glucose homeostasis, and different axial segments of theintestinal mucosa release different hormones in the fasting andpost-prandial state in order to modulate blood glucose in the fastingand post-prandial states, respectively. After a meal, the proximalintestinal mucosa senses the intestine for ingested glucose and releasea collection of hormones in response to this signal. These hormonesinitiate the process of insulin release into the bloodstream after ameal, but they also induce some insulin resistance to prevent thereleased insulin from causing hypoglycemia before the body has a chanceto absorb the ingested glucose. One such hormone that plays a role inthis is GIP. The net effect of distal gut hormones released in responseto a meal, on the contrary, is to both allow the release of more insulinbut also play a role in helping the body now become sensitive to itscirculating insulin. Teleologically, the explanation for this differenceis that enough glucose will have been absorbed by the time nutrientsreach the distal intestine to allow the insulin to begin to function toreduce blood glucose levels (e.g. without significantly riskinghypoglycemia).

In patients with Type 2 Diabetes, a lifetime of exposure to fat andsugar can have led to intestinal changes predominantly in the proximalintestine. These changes are characterized by an excess proximalintestinal hormonal contribution to the fasting and post-prandialglucose homeostasis. The net result of these intestinal changes is tocreate a condition of insulin resistance and impaired glucose tolerance.Treatment of duodenal mucosal tissue with the systems, devices andmethods of the present inventive concepts can be performed to alter theintestinal mucosal hormone production from the region of treated tissue.The treated tissue can then have an altered hormonal secretion patternthat affects blood glucose levels in the fasting and post-prandialstates. The tissue treatment of the present inventive concepts can beperformed to effect duodenal mucosal tissue secretion of GIP and/orGLP-1. The tissue treatment can lead to changes in the blood levels ofGIP and/or GLP-1 (and other gut hormones) that can lead to changes inglucose homeostasis in the fasting and/or post-prandial states. Thetreatment can lead to changes in insulin and/or glucagon secretion fromthe pancreas and/or insulin and/or glucagon levels in the bloodstream.The treatment can lead to changes in pancreatic beta cell functionand/or health through direct hormonal consequences of the treatedduodenal tissue and/or indirectly through improved blood glucose levels.

Treatment of duodenal mucosal tissue can be performed to treat a diseaseand/or disorder selected from the group consisting of: diabetes;pre-diabetes; impaired glucose tolerance; insulin resistance; obesity orotherwise being overweight; a metabolic disorder and/or disease; andcombinations of these. In some embodiments, treatment of duodenalmucosal tissue can be performed to treat a disease and/or disorderselected from the group consisting of: Type 2 diabetes; Type 1 diabetes;“Double diabetes”; gestational diabetes; hyperglycemia; pre-diabetes;impaired glucose tolerance; insulin resistance; non-alcoholic fattyliver disease (NAFLD); non-alcoholic steatohepatitis (NASH); obesity;obesity-related disorder; polycystic ovarian syndrome;hypertriglyceridemia; hypercholesterolemia; psoriasis; GERD; coronaryartery disease (e.g. as a secondary prevention); stroke/TIA; cognitivedecline or dementia (e.g. Alzheimer's); diabetic nephropathy;neuropathy; retinopathy; diabetic heart disease and/or heart failure. Anear full circumferential portion (e.g. approximately 360°, hereinafter“full circumferential”) of the mucosal layer of one or more axialsegments of GI tissue can be treated. In some embodiments, less than360° of one or more axial segments of tubular tissue is treated, such asone or more circumferential portions less than 350°, or between 300° and350°, such as to prevent a full circumferential scar from being createdat the one or more axial segment locations.

Target tissue can be selected to treat two or more patient diseases ordisorders, such as two or more patient diseases or disorders asdescribed herein.

Target tissue can comprise tissue of the terminal ileum, such as totreat hypercholesterolemia and/or diabetes. In these embodiments, thetarget tissue can extend into the proximal ileum and/or the colon.

Target tissue can comprise gastric mucosal tissue, such as tissueregions that produce ghrelin and/or other appetite regulating hormones,such as to treat obesity and/or an appetite disorder.

Target tissue can comprise tissue selected from the group consisting of:large and/or flat colonic polyps; margin tissue remaining after apolypectomy; and combinations of these. These tissue locations can betreated to treat residual cancer cells.

Target tissue can comprise esophageal tissue and/or gastric tissue. Insome embodiments, target tissue comprises cancerous or precanceroustissue treated with a single or multiple energy deliveries, in single ormultiple clinical procedures. In some embodiments, target tissue istreated as a treatment of Barrett's esophagus.

Target tissue can comprise at least a portion of the intestinal tractafflicted with inflammatory bowel disease, such that Crohn's diseaseand/or ulcerative colitis can be treated.

Target tissue can comprise GI tissue selected to treat Celiac diseaseand/or to improve intestinal barrier function.

The treatment assemblies, treatment elements, systems, devices andmethods of the present inventive concepts can be configured to avoidablating or otherwise adversely affecting certain tissue, termed“non-target tissue” herein. Depending on the location of tissue intendedfor treatment (i.e. target tissue), different non-target tissue can beapplicable. In certain embodiments, non-target tissue can comprisetissue selected from the group consisting of: gastrointestinaladventitia; duodenal adventitia; the tunica serosa; the tunicamuscularis; the outermost partial layer of the submucosa; ampulla ofVater (also known as the papilla); pancreas; bile duct; pylorus; andcombinations of these.

In some embodiments, two or more clinical procedures are performed inwhich one or more volumes of target tissue are treated in each clinicalprocedure, such as is described in applicant's co-pending U.S. patentapplication Ser. No. 14/673,565, entitled “Methods, Systems and Devicesfor Performing Multiple Treatments on a Patient”, filed Mar. 30, 2015.For example, a second clinical procedure can be performed at leasttwenty-four hours after the first clinical procedure, such as a secondclinical procedure performed within 6 months of a first clinicalprocedure or a clinical procedure performed after at least 6 monthsafter the first clinical procedure. The first and second clinicalprocedures can be performed using similar or dissimilar methods, andthey can be performed using similar or dissimilar systems and/or devices(e.g. performed with similar or dissimilar treatment elements). Thefirst and second clinical procedures can treat similar or dissimilarvolumes of target tissue (e.g. similar or dissimilar amounts of tissuetreated and/or locations of tissue treated), and they can deliver energyto similar or dissimilar sets of multiple delivery zones. In someembodiments, the first and second clinical procedures can includetreating and/or delivering energy to contiguous and/or overlappingregions of the GI tract either in the circumferential and/or axialdimensions. In other embodiments, the first and second clinicalprocedures can include the treatment of disparate regions of the GItract (such as disparate regions of the duodenum, ileum, and/orstomach). The first and second clinical procedures can be performedusing similar or dissimilar treatment devices. The first and secondclinical procedures can comprise similar or dissimilar deliveries ofenergy to treat the target tissue. The first and second clinicalprocedures can be performed at similar or dissimilar temperatures. Thesecond clinical procedure can be performed based on diagnostic resultscollected after the first clinical procedure has been performed.

The treatment assemblies, treatment elements and other functionalelements of the present inventive concepts can be configured toautomatically and/or manually expand or traverse in at least one radialdirection. Typical expandable elements include but are not limited to:an inflatable balloon; a radially expandable cage or stent; one or moreradially deployable arms; an expandable helix; an unfurlable compactedcoiled structure; an unfurlable sheet; an unfoldable compactedstructure; and combinations of these. In some embodiments, theexpandable elements can comprise a radially expandable tube, such as asheet of material resiliently biased in a radially expanded conditionthat can be compacted through a furling operation, or a sheet ofmaterial resiliently biased in a radially compact condition that can beexpanded through an unfurling operation. The expandable elements cancomprise a foldable sheet, such as a sheet configured to be folded to beradially compacted and/or to be unfolded to radially expand. In someembodiments, the expandable elements expand to contact tissue, such asto expand to a diameter similar to the diameter of the luminal walltissue into which the expandable element has been placed. In someembodiments, the expandable elements expand to be closer to wall tissue,but remain at a distance (e.g. a fixed or pre-determined distance) fromthe tissue surface, such as when the tissue is subsequently brought intocontact with all or a portion of the expanded assembly (e.g. usinginsufflation fluid withdrawal techniques). In some embodiments, theexpandable elements expand to be larger than the diameter of the luminalwall tissue into which the expandable element has been placed, such asto improve the quality of the apposition of the expandable elementagainst the uneven surface of the tissue. In these embodiments, thefully expanded diameter of the expandable elements would be configuredto avoid a diameter large enough to cause lasting mechanical damage tothe apposed tissue and/or to tissue proximate the apposed tissue. Insome embodiments, the expansion of an expandable assembly is monitoredand/or varied (e.g. decreased and/or increased), such as to accommodateor otherwise compensate for peristalsis or other muscle contractionsthat occur in the GI tract (e.g. contractions that occur when a foreignbody is present in the GI tract) and/or varied to accommodate changes inGI lumen diameter imposed by aspects of the procedure itself.

Any device of the present inventive concepts can include one or moretreatment elements configured to deliver energy to one or more deliveryzones, to treat at least a portion of target tissue. Any device caninclude one or more fluid delivery elements, such as one or more nozzlesor needles configured to deliver fluid toward and/or into tissue. Thefluid delivery elements can be constructed and arranged to deliver fluidto perform a function selected from the group consisting of: expandingone or more tissue layers; warming or cooling tissue; removing debris orother substance from a tissue surface; delivering energy to a deliveryzone comprising a continuous or segmented surface; treating targettissue; and combinations of these. Any of the expandable assemblies ofthe present inventive concepts can include one or more other functionalelements, such as are described in reference to the figures herebelow.The treatment elements, fluid delivery elements, and/or other functionalelements can be mounted on, within (e.g. within the wall) and/or insideof an expandable element such as a balloon or expandable cage. In someembodiments, one or more functional elements is not mounted to anexpandable element, such as those attached to a shaft or othernon-expandable treatment device component.

In some embodiments, the treatment device comprises at least onetreatment element configured to deliver energy to a delivery zone suchas to ablate target tissue. Examples of ablation elements include butare not limited to: ablative fluids, such as hot or cold ablative fluidsdelivered to a balloon and/or directly to target tissue; one or morefluid delivery elements configured to deliver ablative fluid directly totarget tissue; an RF and/or microwave energy delivery element such asone or more electrodes; an ultrasonic and/or subsonic transducer such asone or more piezo crystals configured to ablate tissue with ultrasonicor subsonic, respectively, sound waves; a laser energy delivery elementsuch as one or more optical fibers, laser diodes, prisms and/or lenses;a rotating ablation element; a circumferential array of ablationelements; and combinations of these.

The expandable elements comprising balloons of the present inventiveconcepts can be divided into two general categories: those that arecomposed of a substantially elastic material, such as silicone, latex,low-durometer polyurethane, and the like; and those that are composed ofa substantially inelastic material, such as polyethylene terephthalate(PET), nylon, high-durometer polyurethane and the like. A third categoryincludes balloons which include both elastic and inelastic portions.Within the category of elastic balloons, two subcategories exist: afirst sub-category wherein a combination of material properties and/orwall thickness can be combined to produce a balloon that exhibits ameasurable pressure-threshold for inflation (i.e. the balloon becomesinflated only after a minimum fluidic pressure is applied to theinterior of the balloon); and a second sub-category, wherein the balloonexpands elastically until an elastic limit is reached which effectivelyrestricts the balloon diameter to a maximum value. The individualproperties of the balloons in each of these categories can be applied toone or more advantages in the specific embodiments disclosed herein,these properties integrated singly or in combination. By way of exampleonly, one or more of the following configurations can be employed: ahighly elastic balloon can be used to achieve a wide range of operatingdiameters during treatment (e.g. during operation a desired balloondiameter can be achieved by adjustment of a combination of fluidtemperature and pressure); a substantially inelastic balloon or aballoon that reaches its elastic limit within a diameter approximating atarget tissue diameter (e.g. a duodenal mucosal diameter) can be used toachieve a relatively constant operating diameter that will besubstantially independent of operating pressure and temperature; aballoon with a pressure-threshold for inflation can be used to maintainan uninflated diameter during relatively low pressure conditions offluid flow and then achieve a larger operating diameter at higherpressure conditions of flow. Pressure-thresholded balloons can beconfigured in numerous ways. In one embodiment, a balloon is configuredto have a relatively thick wall in its uninflated state, such as tomaximize an electrically and/or thermally insulating effect while theballoon is maintained in this uninflated state. The balloon can befurther configured such that its wall thickness decreases during radialexpansion (e.g. to decrease an electrically and/or thermally insulatingeffect). In another embodiment, a balloon is configured to have arelatively small diameter in its uninflated state (e.g. a diameter thatis small relative to the inner diameter of tubular target tissue such asthe diameter of the mucosal layer of duodenal wall tissue), such as tominimize or completely eliminate apposition between the balloon and thesurrounding tissue to minimize heat, RF and/or other energy transferinto the surrounding tissue until the balloon is fully inflated. Inanother embodiment, a balloon and an ablation system or device areconfigured to circulate a flow of fluid through the balloon (e.g. anelastic balloon or an inelastic balloon) at a sufficiently low enoughpressure to prevent apposition of the balloon or other device componentwith target tissue, such as to pre-heat one or more surfaces of theablation system or ablation device that are in fluid communication withthe balloon. In this configuration, when the balloon or other ablationelement is positioned to deliver energy to target tissue, thetemperature of the balloon or other ablation element will be at adesired level or it will rapidly and efficiently reach the desired levelfor treatment (i.e. minimal heat loss to the fluid path components dueto the pre-heating or pre-cooling). These configurations provide amethod of delivering energy to tissue with an ablative fluid filledballoon. A “thermal priming” procedure can be performed prior to one ormore target tissue treatments, such as to improve thermal response timeof one or more portions of the treatment device. Ablative fluid filledballoon treatment devices as well as thermal priming devices and methodscan be configured as is described in applicant's co-pending U.S.application Ser. No. 14/470,503, entitled “Heat Ablation Systems,Devices and Methods for the Treatment of Tissue”, filed Aug. 27, 2014,the contents of which is incorporated herein by reference in itsentirety.

A fluid evacuation procedure can be performed on one or more internallocations of the treatment devices and/or treatment elements of thepresent inventive concepts, such as when a negative pressure is appliedto purge or otherwise evacuate fluid from one or more locations. A fluidevacuation procedure can be performed prior to a thermal primingprocedure and/or prior to delivering ablative fluid to a treatmentelement.

At times during target tissue treatment when it is desirable toinitiate, increase and/or otherwise modify the treatment of tissue byone or more tissue treatment elements (e.g. a fluid delivery elementdelivering ablative fluid, a mechanically abrasive element, a hot orcold fluid balloon delivering a thermal energy to tissue and/or anelectrode delivering RF energy), the diameter of the treatment assemblyand/or treatment element (e.g. the diameter of a balloon, deployablecage, expandable tube or other expandable assembly) can be increased insitu to move a treatment element closer to target tissue and/or tochange the contact force between the treatment element and the targettissue. At times during treatment when it is desirable to stop orotherwise decrease the amount of tissue treatment, the diameter of thetreatment assembly and/or treatment element can be reduced in situ, suchas to prevent or at least reduce delivery of energy or other treatmentto the target tissue by eliminating or reducing tissue contact of one ormore treatment elements (e.g. electrodes, abrasive surfaces or ablativefluid-filled balloons). For those cases where the native diameter of thetarget tissue varies substantially within a delivery zone, a highlyelastic or compliant balloon or other expandable element can beemployed, such as a balloon or deployable cage which can be adjusted toachieve a wide range of operating diameters.

Alternatively or additionally, to initiate, increase and/or otherwisemodify the treatment of tissue by one or more treatment elements (e.g. afluid delivery element delivering ablative fluid, a mechanicallyabrasive element, a hot or cold fluid balloon delivering thermal energyto or from tissue and/or an electrode delivering RF energy), thediameter of the target tissue can be decreased in situ to move targettissue closer to a treatment element and/or to change the contact forcebetween the target tissue and the treatment element. To stop orotherwise decrease ablation of tissue, the diameter of tissueneighboring a treatment element can be increased in situ, such as toprevent or reduce delivery of energy or other treatment to the targettissue by eliminating or reducing tissue contact of one or moretreatment elements (e.g. electrodes, abrasive surfaces or ablative fluidfilled balloons). The diameter of the tissue proximate a treatmentelement can be increased or decreased, independent of the treatmentassembly diameter, by means of delivering and/or withdrawing a fluid, toand/or from a lumen surrounded by target tissue, such as by usingstandard GI insufflation techniques. Typical insufflation fluids includebut are not limited to: gases such as carbon dioxide or air; liquidssuch as water or saline solution; and combinations of these. Theinsufflation fluids can be introduced through a treatment device,through an endoscope such as an endoscope through which the treatmentdevice is inserted, and/or via another device placed proximate thetarget tissue. Delivery of insufflation fluids can be performed to movetarget tissue away from one or more treatment elements, such as to stoptransfer of energy to target tissue at the end of a treatment of targettissue as described hereabove. Alternatively or additionally, deliveryof insufflation fluids can be performed to manipulate tissue, such as todistend and/or elongate tissue. Removal of these insufflation fluidsand/or the application of a vacuum or other negative pressure can beused to decrease the diameter of the target tissue, such as to bring thetarget tissue in closer proximity to one or more treatment elementsand/or to increase the contact force between target tissue and one ormore treatment elements, also as described hereabove. In this tissuediameter controlled approach, a treatment assembly including a balloonthat can be maintained at a substantially constant diameter can bedesirable, such as a substantially inelastic balloon such as a balloonwith an elastic-limit.

The systems of the present inventive concepts can include one or moretissue expansion devices that comprise one or more fluid deliveryelements, such as one or more needles and/or fluid jets configured todeliver one or more fluids or other injectates to tissue, such as toexpand target tissue and/or tissue proximate the target tissue (e.g.safety margin tissue) prior to treatment of target tissue by a tissuetreatment element. The expanded tissue layer acts as a safety volume oftissue, reducing the specificity of the treatment (e.g. ablation)required and/or the need to protect the underlying non-target tissuefrom damage. In some embodiments, a vacuum pressure can be used tomanipulate tissue and/or to maintain proximity between a portion of atissue expansion device and tissue. The vacuum can be provided by one ormore vacuum sources, such as via one or more operator adjustable vacuumsources.

Referring now to FIG. 1, a schematic view of a system for treating apatient is illustrated, consistent with the present inventive concepts.System 10 can be constructed and arranged to perform the methoddescribed in FIG. 2 herebelow, such as to treat one or more patientdiseases or disorders, also as described herebelow. System 10 comprisestissue treatment device 100 and console 200. Tissue treatment device 100is constructed and arranged to treat target tissue, such as via thedelivery of energy and/or an ablating agent to target tissue. Tissuetreatment device 100 includes connector 103 which operably attaches toconsole 200 at one or more of ports 201 of console 200. In someembodiments, system 10 further comprises tissue expansion device 20which is constructed and arranged to expand one or more layers oftissue, such as one or more layers of target tissue and/or one or morelayers of tissue proximate target tissue (e.g. one or more layers ofsafety-margin tissue). In some embodiments, system 10 further compriseslumen diameter sizing device 30 which is constructed and arranged tocollect information correlated to the diameter of a portion of tubulartissue (e.g. the one, two or more diameters of a GI lumen proximatetarget tissue). In some embodiments, system 10 comprises multi-functiondevice 40, which is constructed and arranged to perform two or morefunctions selected from the group consisting of: tissue treatment (e.g.tissue ablation); tissue expansion; luminal diameter sizing; andcombinations of these. In some embodiments, system 10 comprisesmulti-function device 40, and does not include one or more of: tissuetreatment device 100, tissue expansion device 20 and/or sizing device30.

System 10 can further comprise a body introduction device, such as avascular introducer, laparoscopic port, and/or endoscope 50. System 10can further comprise one or more guidewires, such as guidewires 60 a and60 b (singly or collectively guidewire 60). In some embodiments, one ormore guidewires 60 comprise a guidewire selected from the groupconsisting of: a Savary-Gilliard® 400 cm guidewire, a Dreamwire™guidewire; a super stiff Jagwire™ guidewire; and/or a similar guidewire.In some embodiments, system 10 includes scope attached sheath 80. Sheath80 can comprise an elongate hollow tube which attaches (e.g. in aside-by-side manner) at one or more points along endoscope 50. In someembodiments, sheath 80 comprises the Reach® overtube manufactured byU.S. Endoscopy, or similar.

Tissue treatment device 100, tissue expansion device 20, lumen diametersizing device 30 and multi-function device 40 comprise handles 102, 22,32 and 42, respectively. Handles 102, 22, 32 and 42 each comprise one ormore controls, controls 104, 24, 34 and 44, respectively. Controls 104,24, 34 and 44 are configured to allow an operator to control one or morefunctions of the associated device, such as a function selected from thegroup consisting of: inflate or otherwise expand an expandable assembly;deliver energy; modify energy delivery; deliver an insufflation fluid;insufflate a portion of the GI tract; desufflate a portion of the GItract; deliver an injectate (e.g. into tissue and/or onto the surface oftissue); deliver a tissue expanding fluid (e.g. into tissue); steer thedistal portion of a shaft; translate a control cable or control rod(hereinafter “control rod”); activate a sensor (e.g. record a signal);activate a transducer; activate a functional element; and combinationsof these. In some embodiments, handles 102, 22, 32 and/or 42 cancomprise a user interface configured to control one or more componentsof system 10, such as controls 104, 24, 34 and/or 44, respectively, eachof which can be constructed and arranged to control operation of one ormore of: device 100, device 20, device 30, device 40 and/or console 200.In some embodiments, controls 104, 24, 34 and/or 44 can comprise one ormore user input and/or user output components, such as a componentselected from the group consisting of: screen; touchscreen; light;audible transducer such as a beeper or speaker; tactical transducer suchas a vibratory motor assembly; a keyboard; a membrane keypad; a switch;a safety-switch 206 such as a foot-activated switch; a mouse; amicrophone; and combinations of these.

Handles 102, 22, 32 and 42 each attach to the proximal end of shafts110, 21, 31 and 41, respectively. Shafts 110, 21, 31 and 41 eachtypically comprise a relatively flexible shaft comprising one or moreinternal lumens or other passageways. Shafts 110, 21, 31 and/or 41 cancomprise a lumen, such as lumen 116 of shaft 110 shown, that are sizedand configured to perform a function selected from the group consistingof: provide for the delivery or removal of one or more fluids such asablation fluids, cooling fluids, insufflation fluids, pneumatic fluids,hydraulic fluids and/or balloon expanding fluids; allow over theguidewire delivery of the associated device; surround an electrical wireproviding electrical energy and/or signals; surround an optical fiber;surround a fluid transport tube; slidingly receive a control shaft orother control filament such as a control filament used to expand orcontract an expandable assembly or otherwise modify the shape of aportion of the device; and combinations of these. Shafts 110, 21, 31and/or 41 can comprise a braided or otherwise reinforced shaft or caninclude one or more portions which are reinforced. Shafts 110, 21, 31and/or 41 can comprise a multi-layer construction, such as aconstruction including a braid, a friction-reduced (e.g. PTFE) liner, athermally insulating layer and/or an electrically insulating layer.Shafts 110, 21, 31 and/or 41 can include a bulbous distal end, such asbulbous tip 115 of shaft 110, a circular or oval shaped enlarged endconfigured to improve traversing the innermost tissue of the duodenum orother luminal tissue of the GI tract (e.g. to smoothly advance within alumen whose walls include villi and/or one or more folds). As describedhereabove, shafts 110, 21, 31 and/or 41 can include a guidewire lumen,such as lumen 116 of shaft 110.

Positioned on the distal end and/or on a distal portion of shafts 110,21, 31 and 41 is an expandable tissue treatment assembly, expandableassemblies 130, 25, 35 and 45, respectively. Expandable assemblies 130,25, 35 and 45 are each constructed and arranged to be radially expandedand subsequently radially compacted (each shown in their radiallyexpanded state in FIG. 1), one or more times during use. Each ofexpandable assemblies 130, 25, 35 and 45 can include an expandableballoon, expandable cage, radially deployable arms and/or otherexpandable component.

In some embodiments, tissue treatment device 100, tissue expansiondevice 20, lumen diameter sizing device 30 and/or multi-function device40, with their expandable assemblies 130, 25, 35 and 45 (respectively)in their radially compacted state, are sized and configured to beinserted through a working channel of endoscope 50 and/or sheath 80,after endoscope 50 and/or sheath 80 have been inserted into a patient(e.g. through the mouth and advanced such that their distal end residesin the duodenum or other GI tract location). In some embodiments, tissuetreatment device 100, tissue expansion device 20, sizing device 30and/or multi-function device 40 are sized and configured to be insertedthrough the mouth and into a patient's GI tract alongside endoscope 50.In some embodiments, tissue treatment device 100, tissue expansiondevice 20, lumen diameter sizing device 30 and/or multi-function device40 are sized and configured to be inserted into a patient over one ormore guidewires 60. For insertion over a guidewire, the shafts 110, 21,31 and/or 41 and the distal portions of the associated device 100, 20,30 and/or 40 can comprise sufficient flexibility to traverse the pylorusand enter the duodenum, while having sufficient column and torsionalstrength to be advanced through the duodenum. In some embodiments, oneor more portions of the shafts 110, 21, 31 and 41 have variablestiffness (e.g. stiffer in a proximal portion of the shaft) and/orinclude a lumen configured to accept a stiffening wire, such asstiffening wire 61. Alternatively or additionally, stiffening wire 61can be inserted into endoscope 50 and/or sheath 80, such as tofacilitate their advancement through the stomach and into the duodenum.

Console 200 can be constructed and arranged in a similar fashion toconsole 200 of FIG. 6 described herebelow. Console 200 can comprise anoperator (e.g. clinician) accessible user interface 205. User interface205 can comprise one or more user output and/or user input components,such as a component selected from the group consisting of: screen;touchscreen; light; audible transducer such as a beeper or speaker;tactical transducer such as a vibratory motor assembly; a keyboard; amembrane keypad; a switch; safety-switch 206 such as a foot-activatedswitch; a mouse; a microphone; and combinations of these.

Console 200 can comprise a controller, such as controller 210.Controller 210 can comprise one or more components or assembliesselected from the group consisting of: an electronics module; a powersupply; memory; a microcontroller; a microprocessor; a signal analyzer;an analog to digital converter; a digital to analog converter; a sensorinterface; transducer drive circuitry; software; and combinations ofthese. Controller 210 can comprise one or more algorithms 211, which canbe constructed and arranged to automatically and/or manually controland/or monitor one or more devices, assemblies and/or components ofsystem 10. Algorithm 211 of controller 210 can be configured todetermine one or more tissue expansion and/or tissue treatmentparameters. In some embodiments, algorithm 211 processes one or moresensor signals (e.g. signals from functional elements 139, 29, 39 and/or49 described herebelow) to modify one or more of: volume of tissueexpansion fluid delivered; rate of tissue expansion fluid delivery;temperature of tissue expansion fluid delivery; amount of ablative fluiddelivered; rate of ablative fluid delivery; energy delivered; power ofenergy delivered; voltage of energy delivered; current of energydelivered; temperature of ablative fluid or energy delivered; deviceand/or treatment element location within the GI tract; expandableassembly pressure (e.g. balloon pressure); and combinations of these.Treatment element 135 can deliver energy to a surface of tissue, adelivery zone as described hereabove, which is a subset of the targettissue treated by that energy delivery (e.g. tissue beyond the deliveryzone is also treated due to the conduction of heat or other energy toneighboring tissue). Algorithm 211 can comprise an algorithm configuredto determine a delivery zone parameter such as a delivery zone parameterselected from the group consisting of: anatomical location of a deliveryzone; size of a delivery zone; percentage of a delivery zone to receiveenergy; type of energy to be delivered to a delivery zone; amount ofenergy to be delivered to a delivery zone; and combinations of these.Information regarding a delivery zone parameter can be provided to anoperator of system 10 (e.g. a clinician), such as via user interface205. This information can be employed to set a delivery zone parameter,assist the operator in determining the completion status of theprocedure (e.g. determining when the procedure is sufficiently complete)and/or to advise the operator to continue to treat a pre-specified areaor volume of target tissue. The total area of treatment, number ofdelivery zones, and/or number of treatments during a particularprocedure (any of which can be determined or otherwise assessed viaalgorithm 211) can be defined by clinical and/or demographic data of thepatient.

Console 200 can comprise one or more reservoirs or other sources offluid, such as fluid source 220. Fluid source 220 can be configured toprovide fluid at an ablative temperature (e.g. sufficiently hot or coldto ablate tissue), a treatment neutralizing (e.g. warming or cooling)fluid configured to reduce ablative effects, an insufflation fluid,and/or other fluid. Console 200 can comprise an energy delivery unit,such as EDU 250, configured to deliver energy to treatment element 135and/or one or more other components of system 10, such as one or morecomponents of devices 100, 20, 30 and/or 40. Controller 210, fluidsource 220 and/or EDU 250 can be constructed and arranged similar tocontroller 210, fluid source 220 and/or EDU 250, respectively, of FIG. 6described herebelow.

Console 200 can comprise a pressure assembly, such as pressure assembly225 constructed and arranged to deliver positive pressure or vacuumpressure (e.g. any pressure below another pressure as describedhereabove) to one or more fluid delivery elements or fluid pathways(e.g. lumens) of system 10. Pressure assembly 225 can be constructed andarranged to provide and/or remove fluid to radially expand and/orradially compact, respectively, one or more expandable assemblies, suchas expandable assemblies 130, 25, 35 and/or 45. Pressure assembly 225can comprise one or more pumps or other fluid delivery mechanisms,and/or other pressure or vacuum generators. In some embodiments,pressure assembly 225 is constructed and arranged to provide arecirculating ablative fluid (e.g. hot or cold) to device 100 and/ordevice 40. In these embodiments, pressure assembly 225 can beconstructed and arranged to further provide a recirculating“neutralizing fluid” (e.g. a cooling or warming fluid, respectively, tocounteract the ablative effects of the previously circulated ablativefluid) to balloon 36 and/or 46, respectively. Pressure assembly 225 canbe constructed and arranged similar to vacuum source 230 and/orinflation source 240 of FIG. 6 described herebelow.

Console 200 includes ports 201, which are operably attached to one ormore of: user interface 205 (e.g. safety-switch 206 or another componentof user interface 205), controller 210, fluid source 220 and/or pressureassembly 225. Ports 201 are constructed and arranged to operably attach(e.g. fluidly, electrically, optically, acoustically, mechanicallyand/or otherwise operably attach) to one or more of connectors 103, 23,33 and 43 of devices 100, 20, 30 and 40, respectively. Console 200 canbe constructed and arranged to deliver fluids and/or energy via ports201 to one or more of devices 100, 20, 30 and 40. In some embodiments,an inflation fluid and/or a fluid at an ablative temperature is providedand/or recovered by console 200, such as a fluid at an ablativetemperature delivered to expandable assembly 130 of tissue treatmentdevice 100 and/or expandable assembly 45 of device 40. In someembodiments, insufflation, pneumatic and/or hydraulic fluids aredelivered and/or recovered by console 200 via ports 201. In someembodiments, an injectate 221 is delivered by console 200, such as isdescribed herebelow in reference to tissue expansion device 20 andmulti-function device 40. In some embodiments, one or more control rods(not shown) are translated (e.g. advanced and/or retracted) within oneor more lumens or other openings of device 100, 20, 30 and/or 40, suchas to expand a cage, deploy a radially deployable arm, change the shapeof an assembly, translate an assembly, rotate an assembly and/orotherwise control the position, shape and/or configuration of anassembly of system 10.

Console 200 can provide energy to, send information to and/or record asignal from one or more other elements of device 100, such as functionalelements 139, 29, 39 and/or 49 described herebelow.

Tissue treatment device 100 is constructed and arranged to treat targettissue of a patient. In some embodiments, tissue treatment device 100 isconstructed and arranged similar to tissue treatment device 100 or 100′of FIG. 6 described herebelow. Tissue treatment device 100 compriseshandle 102 which attaches to a proximal end of shaft 110 and includesconnector 103 for operable attachment to console 200 (e.g. at a port201). Positioned on the distal end or on a distal portion of shaft 110is expandable assembly 130. Expandable assembly 130 can comprise anenergy delivery element or other treatment element 135, such as anenergy delivery element configured to deliver thermal, electrical,light, sound and/or ablative chemical energy to target tissue. In someembodiments, treatment element 135 comprises a mechanical abraderconfigured to treat tissue through abrasion. In some embodiments,expandable assembly 130 comprises a balloon 136 which can be configuredto receive one or more expansion and/or ablative fluids. Balloon 136 cancomprise a compliant balloon, a non-compliant balloon and/or apressure-thresholded balloon, and/or balloon 136 can otherwise beconstructed and arranged as described in detail hereabove. In someembodiments, balloon 136 is constructed and arranged similar to balloon136 of FIGS. 4A-C, described herebelow.

Via connector 103, console 200 can provide and/or remove one or morefluids to and/or from one or more lumens or other flow pathways ofdevice 100, such as fluid provided by fluid source 220 and/or propelledby (i.e. delivered and/or removed by) pressure assembly 225. Console200, via EDU 250, can be configured to provide energy to one or moretreatment elements of device 100, such as energy contained in fluid atan ablative temperature (hot and/or cold), electrical energy (e.g. RF ormicrowave energy), light energy (e.g. laser light energy), or soundenergy (e.g. subsonic or ultrasonic sound energy). In some embodiments,console 200 provides a fluid configured to treat target tissue withdirect contact, such as an ablating agent (e.g. a sclerosant or otherchemically ablative agent) and/or a fluid at an ablative temperature,either or both delivered directly to a target tissue surface.

In some embodiments, treatment element 135 comprises a fluid at anablative temperature provided by console 200. In these embodiments,treatment element 135 can comprise a sufficiently hot fluid that isintroduced into balloon 136 for a first time period to ablate targettissue, after which cold fluid is introduced into balloon 136, for asecond time period, to remove heat from tissue (e.g. remove heat fromtarget tissue and/or non-target tissue to reduce the ablation effect).Alternatively treatment element 135 can comprise a sufficiently coldfluid that is introduced into balloon 136 for a first time period toablate target tissue, after which a higher temperature fluid isintroduced into balloon 136, for a second time period, to warm tissue(e.g. warm target tissue and/or non-target tissue to reduce the ablationeffect). Both the ablative and ablation-reducing fluids can be providedby console 200. Alternatively or additionally, a cooling or warmingfluid can be introduced prior to the delivery of the ablative fluid intoballoon 136, as described herebelow. These fluids can be provided in arecirculating manner as described in applicant's co-pending applicationU.S. patent application Ser. No. 14/470,503, entitled “Heat AblationSystems, Devices and Methods for the Treatment of Tissue”, filed Aug.27, 2014, the content of which is incorporated herein by reference inits entirety. Alternatively or additionally, these fluids can beprovided in a single bolus manner as described in applicant's co-pendingapplication International Patent Application Serial NumberPCT/US2014/055514, entitled “Systems, Method and Devices for Treatmentof Target Tissue”, filed Sep. 12, 2014, the content of which isincorporated herein by reference in its entirety. In some embodiments,thermal ablation is performed using system 10 as described herebelow inreference to the method of FIG. 2, or the system 10 of FIG. 6.

In some embodiments, target tissue and/or tissue proximate the targettissue is cooled, heated and subsequently cooled again. In theseembodiments, target tissue and/or tissue proximate the target tissue canbe cooled during at least a portion of a first step, such as a firststep including supplying a first fluid (e.g. a recirculating fluid) toexpandable assembly 130 for a first time period (e.g. a duration ofapproximately 15-30 seconds), wherein the first fluid is supplied at acooling temperature (e.g. continuously supplied by fluid source 220 at atemperature of approximately 5° C. to 25° C., such as between 10° C. and25° C. or between 15° C. and 25° C.). In a subsequent second step,target tissue and/or tissue proximate the target tissue can be heated(e.g. ablated) during at least a portion of the second step, such as asecond step including supplying a second fluid (e.g. a recirculatingfluid) to expandable assembly 130 for a second time period (e.g. aduration of approximately 8-15 seconds), wherein the second fluid issupplied at a heat ablating temperature (e.g. continuously supplied byfluid source 220 at a temperature of approximately 85° C.-95° C.). In asubsequent third step, target tissue and/or tissue proximate the targettissue can be cooled during at least a portion of the third step, suchas a third step including supplying a third fluid (e.g. a recirculatingfluid) to expandable assembly 130 for a third time period (e.g. aduration of approximately 15-30 seconds), wherein the second fluid issupplied at a cooling temperature (e.g. continuously supplied by fluidsource 220 at a temperature of approximately 5° C. and 25° C., such asbetween 10° C. and 25° C. or between 15° C. and 25° C.). In someembodiments, other temperatures and/or durations for each heating orcooling cycle are used. In some embodiments, the second time period inwhich a hot fluid is supplied to expandable assembly 130 comprises atime less than the first time period and/or the third time period. Insome embodiments, the temperature of the fluid supplied to expandableassembly 130 during the first time period and/or the third time periodis at least 18° C. less and/or least 60° less than the temperature ofthe fluid supplied to expandable assembly 130 during the second timeperiod. In some embodiments, the first temperature and the thirdtemperature comprise a similar temperature.

In some embodiments, treatment element 135 comprises one or more energyor other treatment delivery elements positioned in, on and/or withinexpandable assembly 130. Treatment element 135 can comprise one or moreenergy delivery elements configured to deliver energy to target tissue,such as an energy delivery element selected from the group consistingof: a fixed or recirculating volume of fluid at a high enoughtemperature to ablate tissue; a fixed or recirculating volume of fluidat a low enough temperature to ablate tissue; one or more thermal energydelivery elements such as one or more elements configured to deliverheat energy or cryogenic energy; an array of electrodes such as an arrayof electrodes configured to deliver radiofrequency (RF) energy; one ormore electromagnetic energy delivery elements such as one or moreelements configured to deliver microwave energy; one or more opticalelements configured to deliver light energy such as laser light energyto tissue; one or more sound energy delivery elements such as one ormore elements configured to deliver subsonic and/or ultrasonic soundenergy; one or more chemical or other agent delivery elements; andcombinations of these. In some embodiments, tissue treatment device 100is constructed and arranged to deliver RF energy, such as is describedin applicant's co-pending U.S. patent application Ser. No. 14/609,332,entitled “Electrical Energy Ablation Systems, Devices and Methods forthe Treatment of Tissue”, filed Jan. 29, 2015; and/or to deliverablative fluid directly to tissue, such as is described in applicant'sco-pending application U.S. patent application Ser. No. 14/609,334,entitled “Ablation Systems, Devices and Methods for the Treatment ofTissue”, filed Jan. 29, 2015; the contents of which are eachincorporated herein by reference in their entirety.

In some embodiments, tissue treatment device 100 is further constructedand arranged to provide geometric information (e.g. diameterinformation) of a luminal structure such as the duodenum. In theseembodiments, device 100 and expandable assembly 130 can be constructedand arranged similar to expandable assembly 35 and lumen diameter sizingdevice 30 described herebelow.

In some embodiments, system 10 comprises one or more devices forexpanding target tissue or tissue proximate target tissue, such astissue expansion device 20. In some embodiments, target tissue to betreated comprises mucosal tissue and the tissue to be expanded comprisessubmucosal tissue proximate the mucosal tissue to be treated. In someembodiments, tissue expansion device 20 is constructed and arrangedsimilar to device 20 or device 100 described herebelow in reference toFIG. 6. In some embodiments, tissue expansion device 20 is constructedand arranged similar to a tissue expansion device described inapplicant's co-pending International Patent Application Serial NumberPCT/US2015/022293, entitled “Injectate Delivery Devices, Systems andMethods”, filed Mar. 24, 2015, the content of which is incorporatedherein by reference in its entirety. Tissue expansion device 20 can beconfigured to expand a full or partial circumferential segment ofluminal wall tissue, such as to expand one or more layers of submucosaltissue in the duodenum or other luminal portion of the GI tract. Tissueexpansion device 20 can be configured to expand multiple segments of GItract tissue, such as multiple relatively contiguous segments ofsubmucosal tissue expanded as is described in detail herebelow inreference to FIG. 2.

Tissue expansion device 20 comprises handle 22 which attaches to aproximal end of shaft 21 and includes connector 23 for operableattachment to console 200. Positioned on the distal end or on a distalportion of shaft 21 is expandable assembly 25. Expandable assembly 25can comprise an expandable cage, radially deployable arms and/or anexpandable balloon such as balloon 26 shown. Balloon 26 can comprise acompliant balloon, a non-compliant balloon and/or a pressure-thresholdedballoon, and/or balloon 26 can otherwise be constructed and arranged asdescribed in detail hereabove. Balloon 26 can comprise atissue-contacting length of between 20 mm and 26 mm, such as atissue-contacting length of approximately 23 mm. Balloon 26 can comprisea wall thickness of between 0.0002″ and 0.0010″, such as a wallthickness of approximately 0.0005″. Expandable assembly 26 can beconfigured to expand to a diameter between 27.5 mm and 37.5 mm, such asa diameter of approximately 32.5 mm. Expandable assembly 25 can beconfigured to be expanded via control 24 and/or via user interface 205of console 200 (e.g. inflated and deflated by delivery and removal,respectively, of air, water and/or other fluids by console 200).

Expandable assembly 25 comprises one or more fluid delivery elements 28.The one or more fluid delivery elements 28 can each comprise an elementselected from the group consisting of: needle such as a straight needleor a curved needle; water jet (also referred to as fluid jet);iontophoretic fluid delivery element; and combinations of these. The oneor more fluid delivery elements 28 are configured to deliver injectate221 and/or another fluid to tissue when expandable assembly 25 isexpanded (e.g. at least partially expanded with inflation fluid providedby console 200), positioning the fluid delivery elements 28 proximate(e.g. in contact with or close to) tissue to be expanded, such asluminal wall tissue of the GI tract.

The one or more fluid delivery elements 28 can be configured to beadvanced (e.g. advanced into tissue) and retracted via control 24 ofdevice 20. The one or more fluid delivery elements 28 can be positionedin one or more ports 27, as shown in FIG. 1. In some embodiments, avacuum provided by console 200 causes tissue to enter each port 27, suchthat each fluid delivery element 28 can inject fluid (e.g. injectate221) into the captured tissue (e.g. tissue positioned on and/or withinport 27, and/or frictionally engaged by port 27). In some embodiments,tissue is captured within port 27 such that fluid delivery element 28can inject fluid (e.g. injectate 221) into the captured tissue withoutfluid delivery element 28 having to extend radially beyond theassociated port 27. By fluid delivery element 28 remaining within port27, risk of fluid delivery element 28 and/or injectate 221 penetratingthrough the outer surface of the GI tract is prevented or at leastsignificantly reduced. In these embodiments, fluid can be delivered intotissue by fluid delivery element 28 with or without advancement of fluiddelivery element 28 into the captured tissue. In some embodiments, fluiddelivery elements 28, ports 27 and/or other portions of tissue expansiondevice 20 are constructed and arranged similar to the tissue expansiondevices described in applicant's co-pending International PatentApplication Serial Number PCT/US2015/022293, entitled “InjectateDelivery Devices, Systems and Methods”, filed Mar. 24, 2015, the contentof which is incorporated herein by reference in its entirety.

In some embodiments, expandable assembly 25 comprises 3 or more fluiddelivery elements 28 arranged in a circumferential pattern, such as 3fluid delivery elements 28 arranged along a circumference and separatedby approximately 120°. The multiple fluid delivery elements 28 can beconfigured to be advanced individually (e.g. via multiple controls 24),or simultaneously (e.g. via a single control 24). In some embodiments,two fluid delivery elements 28 are separated by approximately 180°. Insome embodiments, four fluid delivery elements 28 are separated byapproximately 90°.

In some embodiments, system 10 includes injectate 221 which can beprovided by console 200 to device 20, and delivered into tissue by theone or more fluid delivery elements 28. Injectate 221 can comprise amaterial selected from the group consisting of: water; saline; a fluidwith a dye such as a visible dye such as indigo carmine; methylene blue;India ink; SPOT™ dye; a gel; a hydrogel; a protein hydrogel; a fluidcontaining a visualizable media such as a media visualizable under X-raysuch as a radiopaque powder (e.g. tantalum powder), ultrasound imagingand/or magnetic resonance imaging; and combinations of these.

In some embodiments, device 20 and/or console 200 are configured toreduce the fluid (e.g. liquid or gas) in balloon 26 as injectate 221 isdelivered into tissue such as submucosal tissue, such as to preventexcessive force being applied to tissue proximate the expanding tissue(i.e. due to the decreasing luminal diameter proximate the expandingtissue in contact with balloon 26). In some embodiments, system 10 isconstructed and arranged to inflate balloon 26 to a first targetpressure, such as a pressure of approximately 0.7 psi. Injectate 221 isdelivered via fluid delivery elements 28 to submucosal tissue (e.g.simultaneously or sequentially). Fluid contained within balloon 26 canbe removed or added to maintain the pressure at or below a second targetpressure, for example a pressure higher than the first target pressuresuch as a pressure between 0.8 psi and 0.9 psi. Fluid of up to 10 ml canbe injected while maintaining the second target pressure (e.g. no morethan the second target pressure) in the balloon (e.g. by decreasing theamount of fluid in the balloon to cause approximately 1 mm steps ofdiameter decrease of balloon 26).

In some embodiments, tissue expansion device 20 is further constructedand arranged to provide geometric information (e.g. diameterinformation) of one or more axial segments of a luminal structure suchas the duodenum. In these embodiments, device 20 and expandable assembly25 can be constructed and arranged similar to lumen diameter sizingdevice 30 and expandable assembly 35, respectively, described herebelow.

In some embodiments, system 10 comprises one or more separate devicesfor estimating or otherwise measuring (e.g. “sizing”) the diameter ofluminal tissue, such as lumen diameter sizing device 30. Sizing device30 is constructed and arranged to be placed into one or more locationsof the GI tract or other internal location of the patient and measurethe diameter or other geometric parameter of tissue. In someembodiments, sizing device 30 is constructed and arranged similar todevice 30 or device 100 described herebelow in reference to FIG. 6.Sizing device 30 can be configured to measure the diameter of multiplelocations of GI tract tissue, such as multiple diameters along thelength of one or more axial segments of the duodenum or other intestinallocation.

Device 30 comprises handle 32 which attaches to a proximal end of shaft31 and includes connector 33 for operable attachment to console 200.Positioned on the distal end or on a distal portion of shaft 31 isexpandable assembly 35. Expandable assembly 35 can comprise anexpandable cage, balloon 36, or other expandable sizing elementconstructed and arranged to measure the inner surface diameter oftubular tissue, such as a diameter of the duodenum or jejunum. Balloon36 can comprise a compliant balloon, a non-compliant balloon and/or apressure-thresholded balloon, and/or balloon 36 can otherwise beconstructed and arranged as described in detail hereabove. Expandableassembly 35 can be configured to be expanded via control 34 and/or viauser interface 205 of console 200 (e.g. inflated and deflated bydelivery and removal, respectively, of fluids by console 200).

Fluids delivered by console 200 to balloon 36 (e.g. fluids supplied byfluid source 200) can be provided at one or more predeterminedpressures, or pressure profiles. Diameter measurements can beaccomplished by performing a visualization procedure (manual orautomated) that assesses balloon 36 diameter. Alternatively oradditionally, balloon 36 can be controllably filled with a fluid, andcontroller 210 can include an algorithm that correlates the fluid volumeand/or fluid pressure to the diameter of tubular tissue in contact withthe balloon. In some embodiments, subsequent selection (e.g. devicemodel or size selection) and/or expansion diameter (e.g. inflateddiameter chosen for sufficient apposition) of expandable assemblies 130,25 and/or 45 of devices 100, 20 and/or 40, respectively, can bedetermined using the information provided by sizing device 30 and/orconsole 200. In some embodiments, device 30 performs a sizing procedureas described herebelow in reference to FIG. 2.

In some embodiments, expandable assembly 35 comprise a balloon orexpandable cage including two or more electrodes configured to provide atissue impedance measurement whose value can be correlated to a level ofapposition of expandable assembly 35, and whose expanded diameter (e.g.visually or otherwise measured) correlates to a diameter of tubulartissue in contact with the expandable element. Alternatively oradditionally, expandable assembly 130 of device 100, expandable assembly25 of device 20 and/or expandable assembly 45 of device 40 can be usedto measure a diameter of the inner surface of tubular tissue, such ashas been described hereabove in reference to expandable assembly 35 anddevice 30.

In some embodiments, system 10 comprises one or more devices, such asmulti-function device 40 shown, that are constructed and arranged toperform two or more functions selected from the group consisting of:treat target tissue such as to deliver energy or otherwise ablate targettissue; expand tissue such as to expand one or more layers of submucosaltissue; and determine or estimate a diameter of a lumen of tubulartissue; and combinations of these. Multi-function device 40 isconstructed and arranged to be placed into one or more locations of theGI tract or other internal location of the patient and perform two ormore of the functions listed above. In some embodiments, multi-functiondevice 40 is constructed and arranged similar to device 100 describedherebelow in reference to FIG. 6. Multi-function device 40 can beconfigured to perform the multiple functions at multiple axial segmentsof the GI tract, such as multiple relatively contiguous axial segmentsof the duodenum as is described herebelow in reference to FIG. 2.

Device 40 comprises handle 42 which attaches to a proximal end of shaft41 and includes connector 43 for operable attachment to console 200.Positioned on the distal end or on a distal portion of shaft 41 isexpandable assembly 45. Expandable assembly 45 can comprise anexpandable cage, balloon 46, or other expandable element constructed andarranged to be position in apposition with and/or in close proximity tothe inner wall of tubular tissue, such as tissue of the duodenum orjejunum. Balloon 46 can comprise a compliant balloon, a non-compliantballoon and/or a pressure-thresholded balloon, and/or balloon 46 canotherwise be constructed and arranged as described in detail hereabove.Expandable assembly 45 can be configured to be expanded via control 44and/or via user interface 205 of console 200 (e.g. inflated and deflatedby delivery and removal, respectively, of fluids by console 200).

Expandable assembly 45 can comprise treatment element 135′, which cancomprise a fluid at an ablative temperature delivered into to expandableassembly 45 by console 200 and/or an energy delivery element permanentlypositioned on, in and/or within expandable assembly 45 (e.g. an energydelivery element configured to deliver thermal energy, electricalenergy, light energy, sound energy and/or chemical energy as describedherein). In some embodiments, treatment element 135′ comprises amechanical abrader configured to treat tissue through abrasion. In someembodiments, treatment element 135′ is constructed and arranged similarto treatment element 135 of device 100 of FIG. 1.

Expandable assembly 45 can comprise one or more elements configured toexpand tissue, such as fluid delivery elements 48. Fluid deliveryelements 48 can each be positioned within one or more ports 47 as shown.Fluid delivery elements 48 and ports 47 can be constructed and arrangedas described hereabove in reference to fluid delivery elements 28 andports 27, respectively, of device 20 of FIG. 1.

Devices 100, 20, 30 and/or 40 can comprise one or more functionalelements, such as functional elements 139, 29, 39, 49, respectively,shown positioned in, on and/or within in expandable assemblies 130, 25,35 and 45, respectively. Alternatively, functional elements 139, 29, 39and/or 49 can be located at a different location of the associateddevice, such as in, on and/or within the associated shaft and/or handleof the device. In some embodiments, one or more functional elements 139,29, 39 and/or 49 comprise a sensor, such as a sensor selected from thegroup consisting of: temperature sensor such as a thermocouple,thermistor, resistance temperature detector and optical temperaturesensor; strain gauge; impedance sensor such as a tissue impedancesensor; pressure sensor; blood sensor; optical sensor such as a lightsensor; sound sensor such as an ultrasound sensor; electromagneticsensor such as an electromagnetic field sensor; visual sensor; andcombinations of these. Alternatively or additionally, one or morefunctional elements 139, 29, 39 and/or 49 comprise a transducer, such asa transducer selected from the group consisting of: a heat generatingelement; a drug delivery element such as an iontophoretic drug deliveryelement; a magnetic field generator; an ultrasound wave generator suchas a piezo crystal; a light producing element such as a visible and/orinfrared light emitting diode; a motor; a vibrational transducer; afluid agitating element; and combinations of these. Functional elements139, 29, 39 and/or 49 can be electrically connected to EDU 250 (e.g. toreceive power, send signals and/or receive signals), such as via anelectrical connection provided by ports 201. Functional elements 139,29, 39 and/or 49 can send or receive signals from controller 210 ofconsole 200, such as one or more sensor signals used to control ablationenergy provided by console 200. Functional elements 139, 29, 39 and/or49 can be activated and/or otherwise controlled via controls 104, 24, 34and/or 44, respectively. Alternatively or additionally, user interface205 of console 200 can be configured to control functional elements 139,29, 39 and/or 49.

In some embodiments, console 200 comprises one or more functionalelements 209, comprising a sensor or transducer as described hereabove.Functional element 209 can comprise one or more pressure sensors, suchas one or more pressure sensors configured to provide a signal used toregulate fluid delivery provided to one or more of devices 100, 20, 30and/or 40, and/or fluid extraction from one or more of devices 100, 20,30 and/or 40. Functional element 209 can comprise one or moretemperature sensors, such as one or more temperature sensors thatprovide a signal used to regulate temperature of one or more fluids ofconsole 200.

In some embodiments, system 10 comprises one or more agents configuredto be delivered to the patient, such as agent 420. Agent 420 can bedelivered by one or more of devices 100, 20, 30, 40 and/or 50, or by aseparate device such as a syringe or other medication delivery device.In some embodiments, agent 420 comprises an anti-peristaltic agent, suchas L-menthol (i.e. oil of peppermint). Alternatively or additionally,agent 420 can comprise glucagon and/or buscopan. Alternatively, agent420 can comprise an ablative agent, such as an ablative agent deliveredto a tissue surface, such as a mucosal surface. Agent 420 can bedelivered into the GI tract, such as via endoscope 50, sheath 80 and/ordevices 100, 20, 30 and/or 40. Agent 420 can be delivered systemically,such as via an intravenous or intra-arterial access line, or injecteddirectly into tissue.

As described above, user interface 205 can comprise safety-switch 206such as a foot-activated switch. Safety-switch 206 can be configured toallow a clinician to activate, modify and/or maintain (e.g. maintain inan “on” state) one or more processes of system 10 without having to usehis or her hands (e.g. without having to use a digit of the hand). Insome embodiments, system 10 is constructed and arranged to perform afunction selected from the group consisting of: automatic contraction(e.g. deflation) of expandable assembly 130 if safety-switch 206 is notactivated (e.g. depressed); automatic replacement of ablative fluid(e.g. hot fluid) with neutralizing fluid (e.g. cold fluid) ifsafety-switch 206 is not activated; initiate introduction of ablativefluid (e.g. hot fluid) into expandable assembly 130 by activation ofsafety-switch 206 (e.g. after expandable assembly has been pre-expandedwith cold fluid and user has confirmed proper position for treatment);allow hands-free activation (e.g. initiation) of a treatment step suchthat one or more operators can maintain their hands one or more ofendoscope 50 and/or devices 100, 20, 30 and/or 40; allow hands-freeactivation (e.g. initiation) of a treatment step such that the requirednumber of operators is reduced; cause a function to cease ifsafety-switch 206 is not activated (e.g. depressed); and combinations ofthese.

Each of devices 100, 20, 30 and/or 40 can be provided in one or moresizes, such as one or more lengths of the associated shaft 110, 21, 31and/or 41, respectively, and/or one or more diameters (e.g. expandeddiameter) of the associated expandable assembly 130, 25, 35 and/or 45,respectively. Luminal sizing as described herein or other anatomicalinformation can be used to select the appropriately sized device totreat the patient.

Referring now to FIG. 2, a flow chart of a method of treating targettissue of a patient is illustrated, consistent with the presentinventive concepts. In some embodiments, the method of FIG. 2 isaccomplished using system 10 of FIG. 1 described hereabove, or system 10of FIG. 6 described herebelow. In Step 510, a patient is selected fortreatment. The patient can be selected to treat a patient disease ordisorder selected from the group consisting of: Type 2 diabetes; Type 1diabetes; “Double diabetes”; gestational diabetes; hyperglycemia;pre-diabetes; impaired glucose tolerance; insulin resistance;non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis(NASH); obesity; obesity-related disorder; polycystic ovarian syndrome;hypertriglyceridemia; hypercholesterolemia; psoriasis; GERD; coronaryartery disease (e.g. as a secondary prevention); stroke/TIA; cognitivedecline or dementia (e.g. Alzheimer's); diabetic nephropathy;neuropathy; retinopathy; diabetic heart disease and/or heart failure;and combinations of these. In some embodiments, the patient is selectedto treat two or more of the above diseases or disorders, such as apatient selected to treat both a form of diabetes andhypercholesterolemia.

The patient selected can be taking one or more medicines to treat theirdiabetes. The patient selected can have an HbA1c level between 7.5% and12.0%, between 7.5% and 10%, or between 7.5% and 9.0%. In someembodiments, the patient selected can have an HbA1c level between 6.0%and 12.0%. Patients with higher HbA1c levels and/or other higher diseaseburden can receive more aggressive treatments (e.g. more tissue treatedand/or higher number of repeated treatments over time) as describedherebelow in reference to Step 570.

Patient selection can be based on the current level of one or moreparameters representing one or more various biomarkers or otherrepresentative values of physiologic conditions (e.g. as compared to anaverage among diabetic and/or non-diabetic patients), such as a level ofa parameter selected from the group consisting of: body mass index (BMI)level; waist circumference; HbA1c level; fasting glucose; insulinresistance; liver fibrosis; cholesterol or triglyceride level; durationof years exhibiting type 2 diabetes; fasting C-peptide or C-Peptidestimulation in response to a meal; age; and combinations of these.

Prior to placing any device in the patient, or at any time thereafter(e.g. during or after the procedure), one or more agents can beintroduced into the patient, such as an agent introduced into the GItract directly, such as agent 420 described hereabove in reference toFIG. 1. In some embodiments, agent 420 comprises L-menthol (i.e. oil ofpeppermint) or other agent configured to provide an anti-peristalsiseffect. In these embodiments, a few drops of agent 420 can be placed inan irrigation lumen of an endoscope or other body inserted device with afluid delivery channel. In some embodiments, approximately 8 mL ofL-menthol is mixed with approximately 0.2 mL of Tween 80 (polysorbate80) in approximately 500 mL of distilled water (i.e. to create anapproximately 1.6% solution). Approximately 20 mL of this mixture can besprayed through a working channel of endoscope 50 or more as required todampen peristalsis. In some embodiments, the solution can vary betweenapproximately 1.6% and 3.2%. Tween anchor sorbitan monostearate can beused as an emulsifier.

One or more agents can be delivered once the endoscope or other agentdelivery device enters the duodenum. In other embodiments, agent 420 isdelivered intravenously, and can comprise glucagon and/or buscopan.

In some embodiments, an endoscope is inserted into the patient (e.g.endoscope 50 of FIG. 1). In these embodiments, subsequently inserteddevices can be placed through a working channel of the endoscope and/oralongside the endoscope. In some embodiments, an endoscope and anattachable sheath (e.g. scope attachable sheath 80 of FIG. 1) are bothinserted into the patient, and subsequently inserted devices can beplaced through a working channel of the endoscope, through theattachable sheath and/or alongside the endoscope and the attachedsheath. Each patient inserted device can be inserted over a guidewire.In some embodiments, an endoscope stiffening device is used, such as anendoscope stiffening system provided by Zutron Medical of Lenexa, Kans.,USA.

In Step 520, non-target tissue can be identified. Non-target tissue canbe identified with a visualization device, such as endoscope 50 ofsystem 10 of FIG. 1. The non-target tissue can comprise the ampulla ofVater, also known as the papilla, the pancreas, or other tissue to whichtreatment may adversely affect the patient. Step 520 and/or another stepof the method of FIG. 2 can include marking the non-target tissue (ortissue proximate the non-target tissue), such as with a tattoo, ink orother visualizable substance, such as a visual agent placed in themucosa and/or submucosa in or proximate the ampulla of Vater. In someembodiments, one or more markers similar to marker 195 describedherebelow in reference to FIG. 3 or 5A-E are deployed in the patient toprovide a reference location relative to non-target tissue. Tissueexpansion and/or tissue treatment performed in subsequent steps canavoid the non-target tissue identified and potentially marked (e.g. withone or more markers 195) in step 520.

In Step 530, a tissue expansion device is inserted into the patient.Step 530 can include selecting a particular model of tissue expansiondevice, such as a particular size or other configuration of a tissueexpansion device. In some embodiments, the tissue expansion device isconstructed and arranged similar to device 20 and/or device 40 of FIG. 1described hereabove, or device 100 or device 20 described herebelow inreference to FIG. 6. The tissue expansion device can be inserted over aguidewire, such as a Savary-Gilliard® guidewire or other relativelystiff guidewire. The guidewire can be advanced such that its distal endis in the jejunum. During advancement of the tissue expansion device,the guidewire can be held taut in order to prevent the tissue expansiondevice from forming a loop in the stomach. In some embodiments, thetissue expansion device is inserted through a working channel of anendoscope, such as endoscope 50 of FIG. 1. In other embodiments, thetissue expansion device is inserted alongside an endoscope.

The tissue expansion device is advanced into the duodenum (e.g. over aguidewire). One or more fluid delivery elements of the tissue expansiondevice can be positioned at least 1 cm, but not more than 5 cm or 10 cmfrom the ampulla of Vater, to perform a first tissue expansion orotherwise a most-proximal tissue expansion (i.e. closest to the ampullaof Vater). In some embodiments, one or more fluid delivery elements ofthe tissue expansion device are positioned based on the location of apreviously placed marker, such as marker 195 described hereabove in STEP520. Prior to and/or during insertion, a stiffening wire can be insertedwithin the tissue expansion device. An endoscope can be positionedadjacent the tissue expansion device, such that both distal ends arebeyond the ampulla of Vater (e.g. beyond a tattoo or other marker ormarking identifying the ampulla of Vater, as described herein).

In some embodiments, prior to insertion of the tissue expansion device,a lumen diameter sizing device is inserted to the patient, such asdevice 30 of FIG. 1. Luminal diameter or other information provided bythe sizing device can be used to select and/or control the tissueexpansion device. The sizing device can be placed over a guidewire asdescribed hereabove or it may be delivered through the working channelof an endoscope. Prior to and/or during insertion, a stiffening wire canbe inserted within the sizing device.

The sizing device expandable element (e.g. balloon) is positioned in thepost-papillary duodenum and inflated at a particular location within theduodenum with a fluid (such as air or saline) and the pressure of thefluid within the balloon is determined by a pressure sensor attached tothe proximal end of the device. The volume of delivered fluid can bedetected by the system. The fluid can be delivered slowly, such as untila stable pressure reading of approximately 0.7 psi (or approximately 0.9psi or 2.0 psi) is determined by the pressure sensor (i.e. a thresholdpressure is achieved). The volume of fluid within the balloon at a givenpressure is used to ascertain the lumen diameter by reference-checkingagainst a calibration step performed before the sizing procedure (e.g.via one or more algorithms of system 10 of FIG. 1 or 6). Measurementscan be taken in at least two locations within the duodenum. An algorithmselects an appropriate ablation balloon size for the individual patient.

In Step 540, tissue is expanded. In some embodiments, saline or otherfluid is injected by multiple fluid delivery elements of the tissueexpansion device, such as three needles or other fluid deliveryelements, positioned in a tissue port and spaced approximately 120°apart along a circumference that deliver injectate (e.g. injectate 221of FIG. 1) into tissue. Each injection can comprise at least 1 ml, suchas at least 2 ml, at least 5 ml or at least 8 ml per fluid deliveryelement. Volumes injected by the multiple fluid delivery elements can beselected to achieve near full circumferential expansion of submucosaltissue (e.g. without gaps, full 360° expansion).

Subsequent injections of fluid into tissue can be delivered, such as atan axial separation distance of between 1 cm and 2 cm apart from aprevious injection (e.g. 1 cm to 2 cm distally in the duodenum). In someembodiments, multiple injections are positioned at least 0.5 cm apartalong the axis of the duodenum, such as between 1.0 cm and 5.0 cm apart,such as approximately 1.0 cm, 2.0 cm, 3.0 cm, 4.0 cm and/or 5.0 cm apartfrom one another along the axis of the duodenum. In some embodiments,axial separation of injection sites (i.e. translation distance of thetissue expansion device between injections) can approximate half thelength of a balloon onto which the fluid delivery elements are mounted,such as half the length of balloon 26 of FIG. 1. In some embodiments, aseries of 5-15 sets (e.g. 8-12 sets) of injections (e.g. each setcomprising injections from 2, 3 or more fluid delivery elements) can beperformed by delivering injectate (e.g. a fluid containing avisualizable dye) to the tissue to be expanding and subsequentlytranslating the tissue expansion device to a new axial location (e.g.after proper expansion of tissue is confirmed visually or otherwise).Each advancement and/or retraction of the tissue expansion device can bemade in unison with advancement and/or retraction of an endoscopepositioned alongside the tissue expansion device.

Tissue expansion can begin at a location proximate but distal to theampulla of Vater, such as at a location at least 1 cm distal to but notmore than 5 cm or 10 cm from the ampulla of Vater. A series ofrelatively contiguous, full circumferential submucosal tissue expansionscan be performed (e.g. moving distally), for example up to the Ligamentof Treitz. In alternate embodiments, multiple full circumferentialtissue expansions are performed by moving the tissue expansion devicefrom distal to proximal locations, or in a discontinuous manner.

Volumes of injections and/or axial separation of injection can be chosento avoid axial gaps. After injections, gaps identified circumferentiallyand/or axially (e.g. via endoscope camera, fluoroscope or ultrasoundimaging device), can be filled in as deemed necessary via additionalinjection (e.g. with or without rotation and/or translation of thetissue expansion device)

In some embodiments, the amount of fluid (e.g. liquid such as water orgas such as air) in an expandable assembly supporting the fluid deliveryelements is reduced as the injectate is delivered into tissue, such asto prevent excessive force being applied to tissue proximate theexpanding tissue (i.e. due to the decreasing lumen proximate theexpanding tissue in contact with expandable assembly), such as isdescribed in detail hereabove in reference to FIG. 1.

In some embodiments, a first volume of fluid (e.g. air) is determinedthat causes a balloon of the tissue expansion device to get sufficientapposition with a lumen of the GI tract (e.g. a lumen of the duodenum),such as by measuring pressure achieved within the balloon. The balloonis subsequently compacted (i.e. fluid removed), and filled with a secondvolume that is less than the first volume, and a confirmation of a lowerpressure can be performed. Vacuum is applied within the GI lumen (e.g.via an insufflation port of an endoscope or other inserted device),causing the lumen to collapse onto the balloon without compressing theluminal wall. A second vacuum is applied to one or more tissue ports onthe balloon (e.g. tissue ports 27 of FIG. 1), causing tissue to be drawninto the tissue ports. One or more needles (e.g. fluid delivery elements28 of FIG. 1) can be advanced into the tissue contained in the tissueports, while avoiding the potential of the needles penetrating an outerlayer and/or outside of the GI wall tissue, as has been described indetail hereabove. In some embodiments, tissue is penetrated by the fluiddelivery elements at the time of the application of the vacuum, withoutthe advancement of the fluid delivery element, also as describedhereabove.

Multiple injections (e.g. three injections from three equally separatedfluid delivery elements) can be performed simultaneously orsequentially. A vacuum can be applied prior to delivery of fluid, suchas to draw tissue toward the fluid delivery element (e.g. into threeassociated ports as described in reference to FIG. 1). After fluiddelivery, the vacuum can be removed and the tissue expansion deviceadvanced (or retracted).

The injectate delivered can include an agent that is directlyvisualizable by an operator (e.g. via an endoscope camera or othercamera), radiographically visualizable (e.g. via a fluoroscope or otherX-ray imaging device) and/or ultrasonically reflectable or otherwisevisualizable (e.g. via an ultrasound imaging device), such as aninjectate 221 comprising visualizable material, as described hereabovein reference to FIG. 1. Visualization of the expanded tissue can be usedto determine proper volume of injectate delivered as well as sufficienttissue expansion (e.g. sufficient thickness, axial length and/orcircumferentiality of tissue expansion). The pressure of the expandableassembly (e.g. balloon) or the volume of fluid within the expandableassembly can also be monitored to determine if a proper volume ofinjectate has been delivered to achieve adequate tissue expansion.

In Step 550, the tissue expansion device is removed, for example usingan over-the wire exchange leaving the guidewire in place. An endoscopeand/or sheath can also be removed during this step. In some embodiments,the tissue expansion device is also configured to ablate or otherwisetreat tissue (e.g. in addition to tissue expansion), and the tissueexpansion device remains in place to perform Step 570.

In Step 560, a tissue treatment device is inserted into the patient(e.g. if not already in place to perform the tissue expansion stepdescribed above, such as when the tissue treatment device is of similarconstruction and arrangement to multi-function device 40 describedhereabove in reference to FIG. 1). Step 560 can include selecting aparticular model of a tissue treatment device, such as a particular sizeor other configuration of a tissue treatment device. In someembodiments, the tissue treatment device is constructed and arrangedsimilar to device 100 and/or device 40 of FIG. 1 described hereabove,and/or device 100 of FIG. 6 described herebelow. In some embodiments,prior to selection of the tissue treatment device, a lumen diametersizing device, such as device 30 of FIG. 1, is inserted and used todetermine the size of a tissue treatment device to be used (e.g. toselect a particular diameter of an expandable treatment assembly of thetreatment device).

The tissue treatment device can be placed through an endoscope, such asendoscope 50 of FIG. 1, or through a scope attached sheath, such assheath 80 of FIG. 1. Alternatively or additionally, the tissue treatmentdevice can be placed over a guidewire, such as guidewire 60 of FIG. 1.In some embodiments, the tissue treatment device is placed over the sameguidewire used to introduce the tissue expansion device of Steps530-550. The tissue treatment device can be advanced to the duodenum. Insome embodiments, the tissue treatment device can be advanced to theduodenum over a guidewire without an endoscope in place, subsequent towhich an endoscope can be advanced to a similar location in theduodenum. In some embodiments, prior to and/or during insertion, astiffening wire can be inserted within the tissue treatment device.

In Step 570, target tissue is treated (e.g. ablated) by one or moretreatment elements of the tissue treatment device, such as treatmentelement 135 positioned on expandable assembly 130 of device 100 ofFIG. 1. The target tissue can comprise one or more portions of themucosal layer of the duodenum. Treated tissue can further comprise atleast an inner layer of neighboring submucosal tissue. One or morecircumferential ablations or other treatments can be performed along alength of the GI tract (e.g. along one or more axial segments of the GItract), such as along a length of the duodenum at least 1 cm distal tothe ampulla of Vater, such as at a location at least 1 cm distal to butwithin 3 cm, 5 cm or 10 cm of the ampulla of Vater. In some embodiments,all ablations are performed at least 2 cm or at least 3 cm distal to theampulla of Vater (e.g. tissue within 1 cm, 2 cm or 3 cm of the ampullaof Vater is not ablated). In some embodiments, one or morecircumferential ablations (e.g. a most-proximal duodenal axial segmentablated) is performed based on the position of a previously placedmarker, such as marker 195 described hereabove in STEP 520. In someembodiments, tissue treatments are only performed at locations that havehad submucosal tissue expansion performed and/or confirmed (e.g.visually). In other embodiments, tissue treatments are performed withoutany tissue expansion, avoiding the need for Steps 530-550.

In some embodiments, a thermal treatment is provided by sufficiently hotor cold fluid introduced into a balloon of the tissue treatment deviceto ablate tissue. In other embodiments, different forms of energydelivery or other tissue treatments are performed, as described indetail in reference to system 10 of FIG. 1 or system 10 of FIG. 6.

The tissue treatment device can treat a series of axial segments of GItract tissue comprising lengths between 1 cm and 5 cm each, such asapproximately 3 cm in length each. The tissue treatment device can treata cumulative axial length of GI tract tissue (e.g. an axial length ofduodenal mucosa tissue) of less than or equal to 3 cm, 6 cm, 9 cm, 15cm, or 20 cm. The tissue treatment device can be constructed andarranged to treat more than 3 cm of axial length of duodenal mucosa,such as more than 3.4 cm, more than 6 cm, more than 7 cm, more than 8 cmor more than 9 cm (e.g. approximately 9.3 cm), such as to achieve aclinical benefit for a diabetes or other patient as described herebelowin reference to applicant's clinical study (including the resultspresented in FIGS. 7-28). In some embodiments, at least 10%, 15%, 25%,30% and/or 50% of the duodenal mucosa distal to the ampulla of Vater istreated. The axial length and/or overall volume of tissue treated cancorrespond to a patient parameter, such as the longevity of the diseaseor other disease parameter as described in detail herebelow (e.g. higherdisease burden correlating to larger volumes of tissue treated).

In some embodiments, at least 3 axial segments of duodenal mucosaltissue are treated (e.g. sequentially treated), such as with a treatmentelement configured to deliver energy to a delivery zone with a lengthbetween 1.0 cm and 4.0 cm (e.g. tissue contacting length of a balloonfilled with ablative fluid), such as a delivery zone length between 1.9cm and 3.3 cm, or approximately 3 cm in length. In some embodiments, atleast 4 axial segments of duodenal mucosal tissue are treated, such asat least 6 axial segments of duodenal mucosal tissue are treated. Inthese embodiments, the treatment element can be configured to deliverenergy to a delivery zone with a length between 0.7 cm and 2.0 cm (e.g.tissue contacting length of a balloon filled with ablative fluid). Insome embodiments, the treatment element comprises ablative fluiddelivered into a balloon, such as the balloon 136 described herein.Multiple tissue treatments are performed by repositioning the treatmentelement (e.g. treatment element 135 of FIG. 1), which can furtherinclude expanding an expandable assembly (e.g. expandable assembly 130of FIG. 1) onto and/or into which the treatment element treating thetissue can be positioned. Contact between the target tissue and thetreatment element can be accomplished using desufflation techniques tobring the tissue toward the treatment element, as described in detailhereabove. Tissue treatment is performed, such as by filling theexpandable assembly with ablative temperature fluid and/or deliveringany form of energy to the target tissue such as is described herein. Inembodiments where the tissue treatment device is delivered over aguidewire, the guidewire can be retracted (e.g. at least retracted to alocation proximal to the treatment element) prior to any tissuetreatments.

Multiple treatments can be performed by advancing or retracting thetissue treatment element and/or tissue treatment device. In someembodiments, the tissue treatment element is positioned at a distallocation and a series of tissue treatments are performed, such as atleast 3 tissue treatments performed in which the tissue treatment deviceis retracted approximately the length of the tissue contacting portionof the treatment element such as to treat relatively contiguous,non-overlapping, full circumferential axial segments of the duodenum.After each tissue treatment, confirmation of being away from (e.g.distal to) any non-target tissue marked and/or otherwise identified(e.g. in Step 520) can be performed (e.g. be visualizing a previouslyplaced marker 195). In some embodiments, a marker 195 is placed to avoidany damage to the ampulla of Vater. In some embodiments, after threeaxial segments of duodenal mucosa are treated (e.g. treated distally toproximally), an assessment of the linear distance between the mostproximal treatment segment and the ampulla of Vater is performed (e.g.one or more components of system 10 is used to determine the distance).If sufficient length is determined (e.g. the determined distance isabove a threshold), additional (more proximal) axial tissue segments canbe treated. During translation of the tissue treatment device over aguidewire, undesired movement of the guidewire is prevented or otherwisereduced by the operator.

In some embodiments, the system of the present inventive concepts (e.g.system 10 of FIG. 1 or 6) is configured to allow only one ablation per(pre-determined) time period, such as to prevent two ablations withinthe time period such as to prevent repetitive ablation in the same or atleast similar (e.g. overlapping) portions of the GI tract (e.g. rapidtreatment of similar treatment zones).

In some embodiments, the tissue treatment of Step 570 should becompleted within approximately 120 minutes or within approximately 60minutes of the initiation of tissue expansion performed in Step 540,such as within approximately 45 minutes, 30 minutes and/or 20 minutes.Performance of tissue treatment within this time window prevents anunacceptable amount of injectate dissipation from the expanded tissue(e.g. submucosal tissue) space. In some embodiments, the system of thepresent inventive concepts (e.g. system 10 of FIG. 1 or 6) is configuredto prevent a tissue treatment (e.g. ablation) until a submucosalexpansion step has been performed.

The amount of target tissue treated and/or the number of treatmentsperformed can correlate to (e.g. be proportional to) one or more patientconditions (e.g. more severe correlates to more tissue treated and/ormore treatments performed over time). This increased treatment cancomprise an increased axial length of tissue treated (e.g. an increasedcumulative axial length of duodenum ablated or otherwise treated), adeeper depth of treatment and/or a larger number of treatments performedover time in order to achieve a sustained treatment response. Increasedtreatments can correlate to a higher burden of the patient's disease(e.g. relatively long duration since diagnosis, higher HbA1c level thana standard diabetic patient and/or more mucosal hypertrophy than astandard diabetic patient). In some embodiments, the volume of targettissue treated and/or the number of treatments performed is proportionalto the patient's HbA1c level.

In some embodiments, the tissue treatment is modified to avoid creationof a duodenal stenosis or stricture, such as to limit one or more of:amount of energy delivered; peak energy delivered; duration of energydelivered; length of tissue treated; depth of tissue treated; andcombinations of these. In some embodiments, a duodenal stenosis orstricture is treated with balloon dilatation.

In some embodiments, tissue expansion is not performed prior to tissuetreatment. In some embodiments, lumen diameter sizing is not performed,or is performed with a tissue expansion device and/or a tissue treatmentdevice. In some embodiments, a single device is inserted into thepatient to perform two or more of: lumen diameter sizing; tissueexpansion; and tissue treatment; such as a device similar to device 40of FIG. 1.

In Step 580, the tissue treatment device is removed. In addition, anyguidewires, endoscopes, scope attached sheaths, or other inserteddevices are removed.

In Step 590, a step of managing the patient post-procedurally can beperformed. Post-procedure patient management can comprise one or moreof: a liquid diet for at least 1 day, 4 days, 5 days, 7 days or 14 days;a soft diet for at least 1 day, 4 days, 5 days, 7 days, or 14 days; alow sugar and/or low fat diet for at least 1 week, 1 month or 1 year; astandardized diabetic (e.g. ADA) diet for at least 1 week, 1 month or 1year; and nutritional counseling for at least 1 week, 1 month or 1 year.

The therapy provided by the systems, methods and devices of the presentinvention can lead to numerous therapeutic benefit outcomes to thepatient receiving the treatment. In some embodiments, the patient has anoutcome selected from the group consisting of: improvement in HbA1c,fasting glucose and/or post-prandial glucose; at least a 1% improvementin HbA1c; d a resultant HbA1c of less than 7.5%, less than 7%, less than6.5%, or less than 6% (e.g. at a time period after a tissue treatmentprocedure of at least 1 month, 3 months, 6 months or 12 months);improvement in one or more triglyceride levels; improvement in AST, ALT,liver fibrosis panel, liver fibrosis score, NAFLD assessment and/or orNASH assessment; improvement in risk of myocardial infarction, stroke,TIA and/or peripheral vascular disease or diabetic cardiomyopathy;improvement in microvascular disease risk such as nephropathy,retinopathy and/or neuropathy; reduced development of end-stage renaldisease, blindness and/or amputation; reduced insulin requirement (e.g.in patients with insulin-dependent diabetes) or other injectable therapyrequirement; reduced medication requirement (e.g. in patients withdiabetes) either in number of medicines or dosage of medicines; improvedfetal birth outcomes (e.g. in patients with gestational diabetes);improved fertility in patients with polycystic ovarian syndrome and/orreduced hirsutism; weight loss of at least 5% of excess body weight, orat least 10%, 20%, 30% or 40% of excess body weight; reduced bloodpressure; reduced cardiovascular risk; improved diabetes control and/orreduced diabetic complications; reduced obesity and/or reduced weight;reduced cognitive decline or prevention of dementia; and combinations ofthese.

The therapy provided by the systems, methods and devices of the presentinvention can have a clinically significant durability that lasts for atleast 3 months, at least 6 months, at least 1 year or at least 2 years.The durability of the treatment can be enhanced by treating more volumesof tissue, such as by treating deeper and/or longer lengths of duodenalmucosa, or by treating the patient multiple times in the same ordifferent regions of the duodenum, small intestine and/or stomach. Thedurability can be improved by selecting patients with a prior history ofdietary compliance and medication compliance and/or a duration of thedisease within a particular time window such as less than 2 year or 5years, or less than 7 years or 10 years.

The systems, methods and devices of the present invention can beconstructed and arranged to avoid or reduce the likelihood of one ormore adverse events. In some embodiments, pancreatitis is avoided byexcluding the ampulla of Vater while performing tissue expansion (e.g.submucosal tissue expansion) and/or tissue treatment (e.g. hot fluidand/or other tissue ablation). In some embodiments, duodenal stenosisand/or stricture can be avoided by performing one or more of thefollowing: ablating only mucosal tissue proximate expanded submucosaltissue layers; ablating only mucosal tissue proximate submucosal tissuelayers expanded within 15 minutes, 30 minutes or 45 minutes of ablation;avoiding a second ablation to a tissue segment ablated within 24 hours;and treating tissue (e.g. ablating) only when the operator has directvisualization (e.g. endoscopic visualization) and/or other visualization(e.g. via X-ray or ultrasonic visualization devices) of the tissuetreatment element and the tissue being treated.

Applicant has conducted human studies with the systems, methods anddevices of the present inventive concepts.

Included below are results of early studies and associated datacollected through Jul. 18, 2014.

Some patients received treatment of approximately 9 cm of relativelyfull-circumferential axial length of duodenal mucosa (via threeapproximately 3 cm hot fluid balloon-based ablations), and some patientsreceived treatment of less than or equal to 6 cm of relativelyfull-circumferential axial length of duodenal mucosa (via two or lessapproximately 3 cm hot fluid balloon-based ablations).

Early results showed: baseline HbA1c was 9.2% and FPG was 187 mg/dl. 1month post-procedure, HbA1c was reduced by 1.1% in LS-DMR patients(patients receiving duodenal mucosa treatments of approximately 9 cm(e.g. 9.3 cm) of duodenal tissue) but only 0.1% in SS-DMR patients(patients receiving duodenal mucosa treatment of approximately 3 cm(e.g. 3.4 cm) of duodenal tissue, the data representing 12 LS-DMRpatients vs 7 SS-DMR patients, each group at 1 month (p=0.058). By 3months, HbA1c was reduced by approximately 2% in LS-DMR patients but wasunchanged in SS-DMR patients (N=5 in each group at 3 months). FPGreductions in LS-DMR patients were −64 mg/dl and −67 mg/dl at 1 and 3months.

FIG. 7 shows a breakdown of a number of patients who received variousquantities of duodenal axial segment treatments comprising delivery ofheat from an ablative fluid delivered to a balloon-based treatmentassembly. Thirty five patients were treated in a dosimetric evaluationof the systems, methods and devices described herein. In the study, anablation is defined as an axial length of circumferentially ablatedtissue, ablated with a single positioning of the balloon and subsequenthot fluid delivery to the balloon. Ablation dose is defined as the totallength of circumferentially ablated tissue on a single procedural day. Asingle patient received 5 ablations (the highest dose administered), andduodenal stenosis presented as food intolerance and epigastricdiscomfort. After endoscopic balloon dilation, the patient recoveredwithout further issue. This patient with the duodenal stenosis lost asubstantial amount of weight in the 2 weeks after the development ofstenosis (nearly 10 kilograms). Controlled duodenal stenosis may be aneffective means of achieving substantial weight loss with its attendantbenefits on metabolic or obesity-related ailments. Creation of atherapeutic restriction can be performed as described in co-pendingInternational Patent Application Serial Number PCT/US2014/066829, titled“Systems, Devices and Methods for the Creation of a TherapeuticRestriction in the Gastrointestinal Tract”, filed Nov. 21, 2014, thecontent of which is incorporated herein by reference in its entirety.

In some embodiments, the systems, devices and methods of the presentinventive concepts can be configured to deliver at least two ablationsto target tissue (e.g. at least two sequential deliveries of energy orother treatments to different axial segments of GI mucosa), such as todeliver at least three ablations to target tissue. In some embodiments,a minimum and/or maximum amount of duodenal mucosa is treated, such ashas been described hereabove.

FIG. 8 is a table of cumulative demographic information for the first 21patients of the applicant's studies. These baseline characteristics aregeneralizable and relevant to the Type 2 diabetes population.

In some embodiments, the systems, devices and methods of the presentinventive concepts can be configured to treat patients with acharacteristic selected from the group consisting of: duration ofdiabetes less than 10 years; age between 18 yrs and 75 yrs; BMI between20 and 60, such as a BMI between 24 and 40; and combinations thereof.

FIG. 9 is a table of results of applicant's studies, detailing recordeddose dependent improvements in glycemic control. Applicant measuredthree validated measures of glycemic control, Hemoglobin A1c (HbA1c),fasting plasma glucose (FPG), and two hour post-prandial glucose (2hPG).

In some embodiments, the systems, devices and methods of the presentinventive concepts can be configured to provide a therapeutic benefitselected from the group consisting of: a reduction in HbA1c of at least0.7%, 1.0% or 1.5% at three months, such as a reduction of approximately2.18 at three months; an FPG of no more than 150 mg/dl, 126 mg/dl or 100mg/dl, such as an FPG that can result with a reduction of approximately63.5 mg/dl; a 2hPG of no more than 250, 200 or 175, such as an 2hPG thatcan result with a reduction of approximately 103.7; and combinationsthereof.

In some embodiments, an absolute change of at least 0.7%, 1.0%, 1.5%and/or 2.0% in HbA1c is expected. In some embodiments, a relative changeabove an HbA1c target is expected, such as a relative change of at least50%, 75% or 100%, such as when the target HbA1c is an HbA1c ofapproximately 6.5%, 7.0% or 7.5%. It has been reported that a 1%absolute change in HbA1c correlates to a 40% reduction in risk ofmicrovascular complication due to diabetes.

FIG. 10 is a graph illustrating an approximately 2% HbA1c reduction inpatients receiving three or more ablations compared with no change inthose receiving fewer than 3 ablations.

In some embodiments, the systems, devices and methods of the presentinventive concepts can be configured to achieve an HbA1c level at orbelow 7.5%, or 7.0% or 6.5%, such as at a time period of 3 months ormore, such as by ablating a cumulative length of duodenal mucosa greaterthan 6 cm, greater than 7 cm, greater than 8 cm or greater than 9 cm(e.g. via 2, 3 or more ablations as described herein).

FIG. 11 is a graph illustrating a similar reduction in FPG levels, whichremain stable between one and three month post procedure.

FIG. 12 is a graphs illustrating similar improvement in 2hPGmeasurements.

FIG. 13 is a graph of treatment response rates, showing that moreablations correlate to a higher percentage of positive patient outcomes.Responders, or patients with positive clinical results, are defined ashaving an HbA1c reduction of at least 0.7% at 1 month.

FIG. 14 is a graph of HbA1c percentages, measured for at least 120 dayspost treatment, showing a durable treatment effect in four out of fivepatients.

In some embodiments, the systems, devices and methods of the presentinventive concepts can be configured to maintain HbA1c below 7.5% at 150days. Note that 3 out of 4 patients are also on lower levels ofmedications than were being administered prior to the tissue treatmentprocedure.

FIG. 15 is a graph of fasting insulin change data, over 3 months,showing an improvement in the health of the beta cell.

FIG. 16 is a graph of SF-36 Mental value changes, showing improvedpatient satisfaction through better glycemic control.

In some embodiments, the systems, devices and methods of the presentinventive concepts can be configured to cause an improvement in apatient condition as measured by the clinical standard SF-36 HealthSurvey, such as an improvement in the SF-36 Mental Change score of atleast 3 points, at least 5 points or at least 10 points.

FIG. 17 is a graph of weight change in study patients, showing thatweight loss was also noticed in a dose dependent manner.

In some embodiments, the systems, devices and methods of the presentinventive concepts can be configured to achieve at least 3 kg or atleast 4 kg of weight loss.

FIG. 18 is a graph suggesting that weight loss and HbA1c are not wellcorrelated based on 30 day post treatment data.

FIG. 19 is a graph of HbA1c percentage over a twenty six week period,comparing responders R and non-responders NR.

FIG. 20 is a graph of Fasting glucose change (mg/dL) over a twenty sixweek period, comparing responders R and non-responders NR.

FIG. 21 is a graph of the change in the area under the curve of a mixedmeal tolerance test.

FIG. 22 is a graph of three patients exhibiting a large treatmenteffect, a 1.9% HbA1c improvement at 30 days.

FIG. 23 is a table presenting the large effect size of high dose cohortbeing statistically significantly better than low dose cohort.

Human studies using the systems, devices and methods of the presentinventive concepts have demonstrated significant effectiveness, such asat least a 2% HbA1c reduction in numerous patients at 3 months, a strongindication of clinical value for patients with poorly controlled glucoselevels. The studies demonstrated excellent concordance between HbA1c andother surrogate markers such as fasting glucose and post-prandialglucose. The studies also demonstrated clinically meaningful weightloss. In some embodiments, the systems, devices and methods of thepresent inventive concepts can be used to treat naïve patients with anHbA1c of more than 6%, 6.5%, or 7%. The treatment could further includethe administration of metformin. The treatment of the present inventiveconcepts (with or without the administration of metformin or othersingle drug) could provide a therapeutic benefit to the patient betterthan a treatment comprising drug therapy alone (e.g. metformin and/oranother single drug therapy). In some embodiments, metformin and asecond-line drug can be included in the treatment of the presentinventive concepts. Treatment outcomes would include improvement inHbA1c, such as patients who achieve an improvement (i.e. reduction) ofat least 1% in HbA1c and/or patients who achieve a target HbA1c of lessthan or equal to 6.0%, 6.5%, 7.0%, or 7.5%. Treatment can also includereduction in hypoglycemic events, improved quality of life, weight loss,and combinations of the above.

Included below are results of continued studies and associated datacollected through Jul. 8, 2015.

Applicant's continued studies included the recording of various patientparameters affected by the treatment of the present inventive concepts,these parameters including but not limited to: HbA1c, fasting bloodglucose and post prandial glucose. Patients received between one andfive ablations (e.g. two to five sequential ablations performed alongtwo to five axial segments of the duodenum distal to the ampulla ofVater) on a single procedural day. The ablations were delivered by anexpandable balloon filled with hot fluid at an ablative temperature, asdescribed in detail herein. The below data were collected from 39patients with the following patient demographics:

Characteristic Value (N = 39) Duration diabetes-yr   5.9 +/− 2.2 Age-yr 53.7 +/− 7.3  Female sex-N (%)   14 (35.9) Weight-kg  85.1 +/− 12.0Height-cm 165.5 +/− 8.8  BMI-kg/m²  31.0 +/− 3.4 

Procedures were completed using general anesthesia. All patients weredischarged on either the day of procedure (19/39) or after an overnightstay (20/39). The number of patients available (included) for eachfollowup study described in FIGS. 24-28, has the following distribution:

Elapsed Time since 2 14 1 3 6 9 12 Procedure Day Day Month Months MonthsMonths Months # of Pts at 39 39 39 38 34 21 21 Followup

The average baseline HbA1c was 9.5% (SD 1.3%) in 39 patients treatedbetween August 2013 and December 2014. HbA1c was 8.1% (SD 1.3%) 1 monthpost-procedure, 7.3% (SD 1.2%) 3 months post-procedure, and 8.1% (SD1.6%) 6 months post-procedure. These HbA1c improvements in the entirecohort are seen despite substantial masking of treatment effect due tomedication reductions in highly responsive patients in the monthsimmediately after the procedure. The average HbA1c improvement in 21patients at a 1 year followup is 0.5% (despite the fact that 9 out ofthese 21 patients were on reduced glycemic medicines compared to beforetheir procedure).

FIG. 24 represents the average HbA1c (%) in all available (at the timeof followup) subjects treated by the systems, devices and methods of thepresent inventive concepts.

The magnitude of the treatment effect was analyzed as a function oftreated dose (i.e. a dosimetric analysis was performed). Patients whohad approximately 9 cm (e.g. 9.3 cm) of duodenal tissue treated (e.g. inat least three applications of thermal energy to duodenal tissue) werelabeled to have received a “Long Segment DMR” (“LS-DMR”). Patients whohad approximately 3 cm (e.g. 3.4 cm) of duodenal tissue treated (e.g. intwo or less applications of thermal energy to duodenal tissue) werelabeled as “Short Segment DMR” (“SS-DMR”). At 1 month follow up, HbA1cwas reduced by an average of 1.7% (SD 1.0%) in LS-DMR and by 0.7% (SD1.2%) in the SS-DMR (n=28 vs 11 at 1 months). At 3 months follow up,HbA1c was reduced by an average of 2.5% (SD 1.3%) in LS-DMR and by 1.2%(SD 1.8%) in SS-DMR (n=28 vs 10 at 3 months, p<0.05 for LS vs SS).

FIG. 25 represents the average change in HbA1c (%) from baseline inpatients with LS-DMR and SS-DMR (p<0.05 for the difference at 3 months).

These clinical studies did not specify a medication treatment algorithmfor the treating diabetologist to prescribe. Note that the treatingdiabetologist was not made aware of the patients' treatment allocationwhen determining the appropriate post-procedure management strategy. Assuch, clinical decisions with respect to medication adjustments inindividual patients were made but these adjustments were not wellcontrolled with respect to a rigorous efficacy evaluation. By the timeof the six month post-procedure follow up visit, several patientsexperienced changes to their glycemic medications that would be expectedto confound efficacy analysis at later time points (see chart below inparagraph [0289]). In particular, 13 out of 26 LS-DMR patientsexperienced reductions in medications and 1 patient experienced anincrease in medication prescription, compared to 4 with reductions and 3with increases among the SS-DMR patients.

The chart below represents the number of patients in each treatment armwith medication changes preceding the six month post-procedure followupvisit.

Patients with Patients Patients with Treatment reduction in with noincreases in Received glycemic meds med changes glycemic meds LS-DMR 1312 1 SS-DMR 4 3 3

At 6 months, LS-DMR patients experienced a decline in HbA1c of 1.6% (SD1.6%) on average (n=26) despite the fact that 13 of 26 patients hadreductions in glycemic medicines that would be expected to mask themagnitude of the procedure's treatment effect. The impact of medicationreductions is evident in the analysis of fasting plasma glucose (FPG) inLS-DMR patients whose baseline HbA1c was between 7.5% and 10%. Patientswhose meds were unchanged after the procedure (“stable meds” group inleft graph below) retain stable FPG between week 12 and week 24.Patients, whose medicines were reduced, however, experienced a decay intreatment effect, the timing of which is coincident with the timing ofprescribed medication reductions.

FIGS. 26A and 26B represents the average fasting plasma glucose inLS-DMR patients with baseline HbA1c between 7.5% and 10%. The graph onthe left shows FPG in all patients (“all patients”), the subset whoexperienced medication reductions (“meds decreased”) and those whosemedications were held constant through 24 week follow up (“stablemeds”). The graph on the right shows the effect of medication reductionswithin the first 12 weeks (“meds decreased early”) compared to thosewith medication reductions between week 12 and week 24 (“meds decreasedlate”). The timing of medication reductions corresponds to the timing ofworsening FPG measurements.

Analysis of patients on consistent medications with a baseline HbA1c ofbetween 7.5% and 10% revealed a mean HbA1c of 8.6 (SD 0.9; n=7) atbaseline, 6.6 (SD 0.8; n=7) at 3 months, 7.2 (SD 0.6; n=6) at 6 months,and 7.3 (SD 0.3; n=4) at 12 months post procedure. These patients alsoexperienced a reduction of fasting plasma glucose of 32 mg/dl (SD 21) at3 months, 36 mg/dl (SD 24) at 6 months, and 20 mg/dl (SD 15) at 12months.

FIG. 27 represents mean HbA1c in LS-DMR patients with baseline HbA1cbetween 7.5% and 10% and consistent antidiabetic medications. Takentogether, HbA1c measurements and fasting plasma glucose levels in LS-DMRpatients with a baseline HbA1c level between 7.5% and 10% suggestdurability of treatment response through 12 months of follow up.

Patient quality of life was assessed using the SF-36 standardizedquestionnaire. At screening, LS-DMR patients had a physical compositescore (PCS) of 47 (SD 9) and a mental composite score of 46 (SD 11). At6 months, patients in the LS-DMR group saw an increase in PCS of 3.1points (SD 10; n=22) and MCS of 3.4 points (SD 14; n=22; p<0.05). Thedata suggest an improvement in the mental quality of life for poorlycontrolled diabetic patients who received LS-DMR.

Patients received a follow-up endoscopy at 1 month and/or 3 monthspost-procedure per protocol. Of the 19 patients who have received afollow-up endoscopy at 1 month, 4 patients had a reduction in heightand/or width of plicae in the duodenum near the treatment area butotherwise the mucosa appeared to be healing normally with no scarring.No luminal narrowing indicative of stenosis was present in any of the 1month endoscopies. Of the 37 patients who have received a follow-upendoscopy at 3 months, two patients had an endoscopically apparentreduction in height and/or width of plicae in the duodenum near thetreatment area. All other patients had normal endoscopies with themucosa fully healed and no evidence of scarring. No luminal narrowingwas observed in any of the 3 month endoscopies. These results indicatethat the treatment can effectively ablate the mucosa without damage tothe duodenal structure and that the mucosa regrows quickly within theablated region. The reduction in height and width of the plicae may beindicative of a reduction in the mucosal redundancy as part of thenormal healing process.

A second procedure of the present inventive concepts was performed in 3previously treated patients. There were no particular proceduralchallenges or significant adverse events associated with the secondprocedure in these three patients. Two patients had been non-respondersto initial procedure, and their second procedure did not successfullyimprove glycemic control. A third patient had an improvement in glycemiccontrol through 3 months after the first procedure, but this benefit wasnot fully sustained through the 6 month follow up visit. A repeatprocedure was performed in month 8, and the patient has since beenfollowed for six months after the second procedure. 14 months after thefirst procedure, therefore, the patient has an HbA1c of 7.3% (reductionof at least 2%) and a FPG of 100 mg/dl.

FIG. 28 represents HbA1c over time in a single patient receiving twotreatments (at month 0 and month 8, respectively).

The above summary provides clinical data on 39 patients enrolled andtreated in an initial study focused on procedural and patient safety andclinical effectiveness. The results demonstrate that the procedure canbe safely completed with devices performing as intended, that theprocedure can be well tolerated by patients, and that there exists astrong suggestion of significant clinical effectiveness. The limitednumber and transient nature of adverse events suggest that the safetyprofile of the technology and procedure is favorable. Although therewere three adverse events of duodenal stenosis formation, all wereendoscopically treated with non-emergent endoscopic balloon dilationusing techniques familiar to operators and resolved with no long-termsequelae. Other significant potential risks, including pancreatitis,perforation, bleeding, infection, or ulcer, have not been observed. Noevidence for malabsorption, severe hypoglycemia, or late complicationswas found. The experience thus far indicates a safe procedure that canbe well tolerated by patients. Mean HbA1c is reduced in treated patientsdespite net medication reductions in the patient cohort. In addition, astatistically significant dosimetric treatment response is alsoobserved, with LS-DMR patients responding more effectively than SS-DMRpatients. In addition, LS-DMR patients experienced more medicationreductions (to prophylactically avoid hypoglycemia) than SS-DMRpatients. This observation was made despite the fact that neitherpatients nor the treating endocrinologist was aware of the length oftreated tissue in individual patients. Furthermore, 23/27 LS-DMRpatients experienced an HbA1c reduction of at least 1% at 3 months offollow up, compared to 6/10 SS-DMR patients. Patients on consistentmedications with a baseline HbA1c of between 7.5% and 10% showedevidence of a durable response to treatment, with persistent reductionsin HbA1c and fasting glucose through 12 months of treatment follow up.This durable treatment response is observed even without aggressivediabetes management on the part of the treating physician, such as maybe achieved through education, lifestyle recommendations, or aggressivepharmacotherapy. The treatment of the present inventive concepts mayoffer an even more significant and durable clinical effect when coupledwith intensive medical management. The treatment effect does not appearto be weight dependent. Patients did not report any food intolerance orchange in food preference that might explain this HbA1c reduction. Whilepatients lost a small amount of weight, the magnitude of weight loss islikely not enough to explain the degree of HbA1c improvement.Furthermore, there did not appear to be any correlation between themagnitude of HbA1c reduction and weight loss.

In some embodiments, the systems, device and methods of the presentinventive concepts can reduce the need for insulin therapy in a largerproportion of patients, such as to provide durable glycemic control withor without the therapies administered to the patient prior to thetreatment of the present inventive concepts, or with a decrease indosage of one or more previously administered medications.

The systems, devices and methods of the present inventive concepts canbe configured to treat patients with microvascular disease or patientswith a high risk of microvascular disease, such as to improve patienthealth and/or eliminate or otherwise reduce the need for one or moremedications (e.g. one or more insulin medications). The treatment can beconfigured to reduce diabetic retinopathy (e.g. as shown in a reductionin diabetic retinopathy score), proteinuria and/or peripheral neuropathyseverity. Additionally or alternatively, the treatment can be configuredto reduce the effects of macrovascular disease such as myocardialinfarction, stroke, peripheral vascular disease, CV death, andcombinations of these.

Referring now to FIG. 3, a side sectional view of the distal portion ofa tissue treatment device inserted into a curvilinear section ofduodenum is illustrated, consistent with the present inventive concepts.Tissue treatment device 100 comprises shaft 110, a relatively flexible,biocompatible, elongate structure configured for insertion into a bodylumen such as the duodenal lumen shown. Shaft 110 is typically connectedto a handle on its proximal end, not shown but configured to allow anoperator to advance, retract and otherwise manipulate or control device100, such as is described hereabove in reference to device 100 ofFIG. 1. Tissue treatment device 100 can be configured for delivery overa guidewire, via a lumen from a proximal portion of shaft 110 to adistal portion of shaft 110, or via a rapid exchange sidecar or otherlumen in the distal portion of shaft 110 (guidewire lumen and sidecarnot shown but known to those of skill in the art). Shaft 110 is showninserted through introducer 50 which can comprise an endoscope, sheath,vascular introducer, laparoscopic port, or other body introductiondevice.

Tissue treatment device 100 further comprises a treatment assembly,expandable assembly 130, which can include a balloon and/or be ofsimilar construction and arrangement as expandable assembly 130 ofFIG. 1. Fluid at an ablative temperature (i.e. a sufficiently high orlow temperature to ablate tissue), treatment element 135, has beendelivered to expandable assembly 130, as described hereabove, to deliverenergy to one or more portions of a delivery zone and to treat one ormore portions of target tissue.

A marker 195 has been positioned on the wall of the GI tract to be usedas a reference to identify non-target tissue (e.g. a marker placed ontissue in relation to the ampulla of Vater, such as at a location distalto but proximate the ampulla of Vater). Marker 195 can comprise anelement selected from the group consisting of: a visible marker (e.g.visible via camera 52 of endoscope 50); a radiographic marker; anultrasonically visualizable marker; a magnetic marker; ink; dye; andcombinations of these. Marker 195 can comprise multiple markerspositioned in various locations (e.g. various locations used as areference to identify multiple different or similar segments ofnon-target tissue.

Expandable assembly 130 has been positioned in a distal portion ofduodenal tissue, such as a section that includes a previously expandedsegment of submucosal tissue (submucosal tissue expansion not shown).Expandable assembly 130 has been radially expanded such as to contactthe mucosal surface of the duodenum at a discrete tissue segment oftarget tissue, tissue segment TS1 as shown. Tissue segment TS1 islocated distal to a series of sequential tissue segments of targettissue, tissue segments TS2 through TS6 as shown. Expandable assembly130 and treatment element 135 (ablative fluid) are shown in FIG. 3positioned to ablate or otherwise treat tissue segment TS1. Each oftissue segments TS1 through TS6 has a corresponding delivery zone (notshown) to which energy is delivered from expandable assembly 130 tocause the appropriate treatment of target tissue. In some embodiments, aseries of adjoining segments are treated sequentially (i.e. from distalsegment TS1 to each correspondingly more proximal segment TS2 throughTS6 or from proximal segment TS6 to each correspondingly more distalsegment TS5 through TS1). In some embodiments, a complete treatmentcomprises treatment of at least three adjacent segments (e.g. TS1through at least TS3, TS2 through at least TS4, TS3 through at least TS5or TS4 through at least TS6). Alternatively, a non-continuous patterncan be treated (e.g. TS1 followed by TS3 followed by TS2, and the like).In some embodiments, marker 195 is positioned in reference to theampulla of Vater (e.g. proximate the ampulla of Vater), and all segmentsto be treated are positioned distal to the ampulla of Vater, such as canbe determined by visualizing marker 195.

Expandable assembly 130 can be sized to allow positioning in curvedsegments of the GI tract with a minimum radius of curvature, such as acurved segment of the duodenum and/or jejunum with an average radius ofcurvature less than 5 cm over a 75° arc, or less than 3 cm over a 75°arc. In these curved segments (and straighter segments as well),expandable assembly 130 can be expanded without exerting undesired forceonto tissue (e.g. expanded to contact the tissue wall). In someembodiments, expandable assembly 130 is constructed and arranged totreat curved segments of the GI tract and comprises a length less thanor equal to 30 mm, such as less than or equal to 25 mm, less than orequal to 20 mm, or less than or equal to 15 mm.

After treatment of tissue segment TS1, expandable assembly 130 can berepositioned to tissue segment TS2, just proximal to tissue segment TS1,with or without contracting expandable assembly 130 prior to therepositioning. Subsequently, a second tissue treatment (e.g. a secondenergy delivery) can be performed. The steps of repositioning andtreating portions of target tissue are repeated until one or more oftissue segments TS3, TS4, TS5, and TS6 have been treated. In someembodiments, an ablation reducing step is performed after each tissuesegment treatment, such as by delivering a treatment neutralizingcooling fluid after a hot fluid ablation or delivery of a treatmentneutralizing warming fluid after a cool (e.g. cryogenic) ablation, eachas described herein. Alternatively or additionally, a cooling or warmingfluid can be delivered, prior to a heat or cryogenic ablation,respectively, as described herein.

In a single clinical procedure, the combined length of target tissuesegments TS1 through TS6 can represent between 10% and 100% of thelength of the duodenal mucosa length distal to the ampulla of Vater,such as when between 2 and 50 axial segments of tissue receive between 2and 50 energy deliveries from expandable assembly 130 (e.g. ablativefluid 335 is introduced into expandable assembly 130 2 to 50 sequentialtimes). In some embodiments, each of tissue segments TS1 through TS6have a maximum axial length of less than 20 cm, less than 15 cm, lessthan 10 cm, less than 5 cm, less than 3 cm or less than 2 cm. In someembodiments, the cumulative axial length of tissue segments treated,(e.g. two or more of tissue segments TS1 through TS6) is less than 100cm, less than 50 cm, less than 25 cm, or less than 10 cm. In someembodiments, at least 6 cm or at least 9 cm of the duodenum is treated.Alternatively or additionally, other tissue (e.g. other tissue of the GItract) can be treated, such as has been described hereabove.

Target tissue segments TS1 through TS6 typically include common borderor overlapping tissue segments, such as is shown in FIG. 3. While theembodiment of FIG. 3 shows six target tissue segments being treated,more or fewer segments can be treated. In some embodiments, three axialtissue segments are treated (e.g. TS1, TS2 and TS3). In someembodiments, four axial tissue segments are treated (e.g. TS1, TS2, TS3and TS4). In some embodiments, five axial tissue segments are treated(e.g. TS1, TS2, TS3, TS4 and TS5). In some embodiments, all GI tracttissue treated is distal to the ampulla of Vater.

Tissue treatments can be performed in a contiguous manner (e.g. a 1stportion, followed by a 2nd portion whose distal end is proximate theproximal end of the 1st portion, followed by 3rd portion whose distalend is proximate the proximal end of the 2nd portion, etc); however anyorder can be performed. In some embodiments, multiple contiguous ordiscontiguous tissue segments are treated simultaneously. In someembodiments, contiguous tissue segments are treated by device 100continuously, as expandable assembly 130 is relatively continuouslytranslated proximally and/or distally, such as via a manual or automatedretraction and/or advancement, respectively, as is described inreference to FIG. 6 herebelow. In some embodiments, treatment of targettissue is performed as expandable assembly 130 translates at a rate ofat least 1 cm per minute, at least 2 cm per minute, at least 5 cm perminute, or at least 10 cm per minute. In some embodiments, a segment ofnon-treated GI tissue is positioned between two segments of treated GItissue, such as a non-treated segment of GI tissue in a sharp bend.

Referring now to FIGS. 4A, 4B and 4C, perspective, side and end views,respectively, of an expandable element comprising a balloon isillustrated, consistent with the present inventive concepts. Balloon 136comprises an expandable element of the present inventive concepts, whichcan be configured receive a treatment element comprising fluid at anablative temperature for treating target tissue, such as balloon 136 ofFIG. 1 described hereabove. Balloon 136 can be constructed and arrangedof one or more biocompatible materials, such as a material selected fromthe group consisting of: polyethylene terephthalate (PET); nylon; latex;polyurethane; and combinations of these. In some embodiments, balloon136 comprises a wall thickness, Dim G, such as a wall thickness between0.0002″ and 0.0010″, such as a wall thickness of approximately 0.0005″.

In some embodiments, balloon 136 comprises a tissue contacting portionwith a diameter of Dim A as shown. Dim A can comprise a diameter ofapproximately between 16.0 mm and 35.0 mm, such as a diameter between19.0 mm and 32.0 mm. In some embodiments, balloon 136 comprises a tissuecontacting portion, with a length defined by Dim D as shown. Dim D cancomprise a length between 16.0 mm and 35.0 mm, such as a length between19.5 mm and 32.9 mm. In some embodiments, balloon 136 comprises atapered distal end, distal taper DT, which transitions from the tissuecontacting portion with a curved segment, Dim B, with a radius between 7mm and 9 mm, such as a radius of approximately 8 mm. Distal taper DT cancomprise a taper, Dim F as shown, such as a taper between 27° and 33°,such as a taper of approximately 30°. In some embodiments, balloon 136comprises a tapered proximal end, proximal taper PT, which transitionsfrom the tissue contacting portion with a curved segment, Dim C, with aradius between 0.4 mm and 0.6 mm, such as a radius of approximately 0.5mm. Proximal taper PT can comprise a taper, Dim E as shown, such as ataper between 42° and 48°, such as a taper of approximately 45°.

In some embodiments, the tissue contacting portion of balloon 136comprises a surface area of between 1750 mm² and 2150 mm², such as asurface area of approximately 1950 mm². In some embodiments, a system ofthe present inventive concepts (e.g. system 10 of FIG. 1) comprisesmultiple tissue treatment devices (e.g. device 100 of FIG. 1), eachcomprising a balloon 136 with different tissue contacting portionlengths and/or diameters. In these embodiments, the surface area of thetissue contacting portion can comprise a relatively equivalent area foreach device, such as when each tissue contacting portion surface areacomprises an of between 1750 mm² and 2150 mm², such as a surface area ofapproximately 1950 mm². Similar surface areas for the different tissuetreatment device's tissue contacting portions provide the advantage of:similar ablative fluid delivery settings; similar change in balloontemperature with fluid replacement (i.e. between cold and hot water orhot and cold water) to allow a steep “shoulder” of thermal profilewithin the balloon; similar uniformity of thermal profile along theballoon surface such as during the replacement of cold/hot water withone another within the balloon; similar tissue contact along the surfaceof the balloon including in bends of the GI tract.

Balloon 136 can be constructed and arranged to be filled with aparticular volume of fluid (e.g. ablative fluid), such as a volume ofbetween 10 ml and 35 ml, such as a volume between 12.5 ml and 30.0 ml.Balloon 136 can comprise a tubular stem extending from each of distaltaper DT and/or proximal taper PT, such as to facilitate fluidattachment of balloon 136 to a shaft, such as shaft 110 of FIG. 1.

In some embodiments, the systems of the present inventive concepts cancomprise two or more balloons 136, such as a first balloon 136 used in afirst tissue treatment device (e.g. device 100 of FIG. 1 or FIG. 6) anda second balloon 136 used in a second tissue treatment device (e.g.device 100′ of FIG. 6). The first balloon 136 and the second balloon 136can comprise similar or dissimilar properties, such as similar ordissimilar tissue contacting lengths and/or diameters, such as to treatdifferent segments of the GI tract.

Referring now to FIG. 5, a side sectional view of the distal portion ofa tissue treatment device including an agent dispensing element isillustrated, consistent with the present inventive concepts. Tissuetreatment device 100 comprises shaft 110 which includes lumen 116exiting the distal end of shaft 110. Positioned on a distal portion ofshaft 110 is an expandable treatment assembly, expandable assembly 130which includes a tissue treatment element, agent dispensing element136″. Shaft 110 and expandable assembly 130 are constructed and arrangedsuch that shaft 110 can be inserted within and/or alongside anendoscope, such as endoscope 50 of FIG. 1. Lumen 116 and/or anotherlumen of shaft 110 can be constructed and arranged to allowover-the-wire delivery of shaft 110. Shaft 110 can comprise a length(e.g. at least 100 cm) such that expandable assembly 130 can bepositioned proximate the distal end of the duodenum of a patient.

Agent dispensing element 136″ is constructed and arranged to coat orotherwise apply one or more agents to target tissue. Tissue treatmentdevice 100 and/or an associated system 10 can comprise one or moreagents to be delivered by agent dispensing element 136″, such as tissuemodifying agent 135″; described herebelow in reference to FIGS. 5A-5E.Agent dispensing element 136″ can comprise a material configured toexpand, such as an expansion that occurs when agent dispensing element136″ comes into contact with a fluid (e.g. tissue modifying agent 135″or another fluid). Agent dispensing element 136″ can be constructed andarranged to apply one or more tissue modifying agents 135″ to targettissue. Tissue modifying agent 135″ can comprise a chemical or otheragent configured to cause target tissue necrosis or otherwise treattarget tissue. Tissue modifying agent 135″ can comprise an agentselected from the group consisting of: a chemical peeling agent; a mildacid such as glycolic acid; trichloroacetic acid; a mild base; phenol;retinoic acid; and combinations of these.

In some embodiments, agent dispensing element 136″ comprises a materialselected from the group consisting of: a sponge material (e.g. a naturalor synthetic sponge material); a foamed polyurethane; a polyvinylalcohol (PVA) sponge; a hydrogel; a super-absorbent polymer; andcombinations thereof. Shaft 110 further includes lumen 117 which travelsto a proximal portion of shaft 110 and is constructed and arranged toprovide one or more fluids to agent dispensing element 136″.

Device 100 can comprise one or more deployable occluding elements, suchas occluder 193 a, shown positioned within lumen 116 of shaft 110.Device 100 can further include translatable push rod 138 configured tobe advanced to deploy occluder 193 a from the distal end of lumen 116.Occluder 193 a can be configured to radially expand to at leastpartially occlude a segment of the gastrointestinal tract, as describedherebelow in reference to FIGS. 5A-5E, such as to prevent undesiredmigration of tissue modifying agent 135″ to non-target tissue. Occluder193 can comprise one or more expandable materials or elements such as anexpandable balloon and/or an expandable sponge (e.g. similar to agentdispensing element 136″). Occluder 193 can include digestible and/orbiodegradable materials. Occluder 193 can be configured to evacuate thebody via the body's natural digestive system and/or to be removed suchas via a grasping element deployed through an endoscope. In someembodiments, additional occluders 193 can be deployed via rod 138 andlumen 116, such as two occluders 193 positioned at opposite ends of asegment of GI tract to be treated by agent dispensing element 136″, alsoas described herebelow in reference to FIGS. 5A-5E.

Device 100 of FIG. 5 can be included as part of a system, such as system10 of FIG. 1 or FIG. 6. The system can include an agent delivery unit,such as a console 200, configured to deliver one or more agents to agentdispensing element 136″, and the system can include the agent to beapplied onto target tissue, tissue modifying agent 135″. In someembodiments, agent 420 of FIG. 1 comprises tissue modifying agent 135″.

Referring now to FIGS. 5A-5E, side sectional views of a series of stepsfor treating a surface of GI tissue with the tissue treatment device ofFIG. 5 are illustrated, consistent with the present inventive concepts.In FIG. 5A, endoscope 50 has been inserted into a segment of GI tract asshown (e.g. the duodenum). Endoscope 50 includes multiple workingchannels, lumens 51 and 54, and a visualization device, camera 52. Amarker 195 has been positioned on the wall of the GI tract to be used asa reference to identify non-target tissue (e.g. tissue of the ampulla ofVater that should not be treated). Marker 195 can comprise one or moremarkers of similar construction and arrangement and/or placement tomarker 195 of FIG. 3 described hereabove. Marker 195 can be positionedon and/or in tissue using device 100 of FIG. 5 and/or another devicesuch as endoscope 50.

Device 100 of FIG. 5 has been inserted through lumen 51 of endoscope 50and advanced to a location distal to the position of marker 195 asshown. Occluder 193 a is partially deployed from the distal end of shaft110, such as via advancement of rod 138 described hereabove in referenceto FIG. 5. Agent dispensing element 136″ is in its radially compactstate (e.g. prior to introduction of tissue modifying agent 135″).Device 100 can be of similar construction and arrangement to device 100of FIG. 1 or device 100 of FIG. 6. In alternative embodiments, device100 is inserted over a guidewire (e.g. not through endoscope 50) and/orthrough a sheath.

Referring now to FIG. 5B, occluder 193 a has been deployed, and tissuemodifying agent 135″ is being introduced into agent dispensing element136″ such as to partially expand agent dispensing element 136″. Tissuemodifying agent 135″ can be provided via a fluid delivery device (e.g. afluid pump) fluidly attached to lumen 117 shown in FIG. 5. In someembodiments, the fluid delivery device is constructed and arranged as isdescribed herein in reference to console 200 of system 10 of FIG. 1 orto energy delivery unit 250 and/or console 200 of system 10 of FIG. 6.

Referring now to FIG. 5C, agent dispensing element 136″ has been fullyexpanded to contact the wall of the GI segment, and device 100 has beenpartially retracted such that tissue modifying agent 135″ coats thefull-circumferential wall, or at least a partial-circumferentialportion, of the GI segment distal to agent dispensing element 136″.During the retraction of device 100, tissue modifying agent 135″ isprovided (e.g. continuously provided) to agent dispensing element 136″.

Referring now to FIG. 5D, device 100 has been further retracted to aproximal end of the GI segment to be treated. Additionally, flow oftissue modifying agent 135″ to agent dispensing element 136″ has beenstopped, agent dispensing element 136″ has been withdrawn into lumen 51of endoscope 50 (leaving the distal end of shaft 110 extending out ofendoscope 50), device 100 has subsequently been even further retracted,and a second occluding element, occluder 193 b has subsequently beenpartially deployed from the distal end of shaft 110 (e.g. via controlrod 138 in a similar fashion to the deployment of occluder 193 a).

In some embodiments, agent dispensing element 136″ is radiallycompressed prior to capture into lumen 51 (e.g. via application of adehydrating agent, application of a vacuum capture via an advanceablesleeve, and the like). In some embodiments, a second agent (e.g. aneutralizing agent configured to stop and/or reverse the effects oftissue modifying agent 135″) is delivered by agent dispensing element136″ prior to capture of agent dispensing element 136″ into lumen 51.Alternatively or additionally, the neutralizing or other agent can bedelivered via lumen 54. Delivery of a neutralizing agent can beperformed to prevent adverse effect to non-target tissue.

Referring now to FIG. 5E, occluder 193 b has been fully deployed, andendoscope 50 and device 100 have been removed from the patient. Tissuemodifying agent 135″ is present on the inner layer (i.e. mucosal layer)of the GI segment between occluders 193 a and 193 b, such that this fullcircumferential segment can be treated. In some embodiments, the segmentbetween occluders 193 a and 193 b defines the entire segment of tissueto be treated in that clinical procedure. In other embodiments, multiplesegments (e.g. defined by additional occluders 193), can be treated in asingle clinical procedure. In these single segment and multi-segmentembodiments, the amount of target tissue treated with tissue modifyingagent 135″ (e.g. the inner tissue layer between occluders 193 a and 193b as described in reference to FIGS. 5A-5E) can be selected as describedherein (e.g. at least 10%, at least 15%, at least 20%, at least 25%, atleast 30% or at least 50% of the length of the duodenum distal to theampulla of Vater). In some embodiments, the amount of target tissuetreated with device 100 of FIGS. 5 and 5A-5E is selected to cause thetreatment achieved as described hereabove in reference to FIG. 2 andFIGS. 7-28. In some embodiments, the cumulative axial length treated isat least 4 cm, 5 cm, 6 cm, 7 cm, 8 cm or 9 cm of the duodenum.

Referring now to FIG. 6, a schematic view of a system for treatingtarget tissue of a patient is illustrated, consistent with the presentinventive concepts. System 10 includes tissue treatment device 100,which includes shaft 110 mounted on its proximal end to handle 102.Shaft 110 can comprise one or more shafts, such as outer shaft 110 a andinner shaft 110 b, slidingly received by outer shaft 110 a. The distalportion of tissue treatment device 100 has been positioned in a segmentof the GI tract. System 10 can further include tissue expansion device20 and/or console 200, each of which can be of similar construction andarrangement to tissue expansion device 20 and/or console 200,respectively, of FIG. 1. Console 200 can be operably (e.g. fluidly,mechanically and/or electrically) attach to tissue treatment device 100,tissue expansion device 20 and/or another device or component of system10, such as via one or more of ports 201. System 10 is configured totreat target tissue TT, which can include duodenal mucosa or othertissue as described herein to provide therapeutic benefit to thepatient, such as the therapeutic benefits and other results presented inFIGS. 7-18. System 10 can be further configured to deliver an injectateinto target tissue TT to expand tissue proximate target tissue TT(including target tissue TT itself), such as to expand one or morelayers of tissue proximate target tissue TT.

System 10 can be configured to treat one or more patient diseases ordisorders selected from the group consisting of: diabetes; pre-diabetes;impaired glucose tolerance; insulin resistance; obesity or otherwisebeing overweight; a metabolic disorder and/or disease; and combinationsof these. In some embodiments, system 10 can be configured to treat oneor more patient diseases or disorders selected from the group consistingof: Type 2 diabetes; Type 1 diabetes; “Double diabetes”; gestationaldiabetes; hyperglycemia; pre-diabetes; impaired glucose tolerance;insulin resistance; non-alcoholic fatty liver disease (NAFLD);non-alcoholic steatohepatitis (NASH); obesity; obesity-related disorder;polycystic ovarian syndrome; hypertriglyceridemia; hypercholesterolemia;psoriasis; GERD; coronary artery disease; stroke; TIA; cognitivedecline; dementia; diabetic nephropathy; neuropathy; retinopathy;diabetic heart disease; diabetic heart failure; and combinations ofthese.

Treatment of target tissue TT can be performed after expanding targettissue TT and/or after expanding tissue proximate target tissue TT (e.g.expanding a submucosal layer of tissue and subsequently treating theneighboring mucosal layer of tissue). Tissue expansion by device 20 cangreatly alleviate the need for precision of treatment, such as precisionof delivery of energy, precision of debriding or other removal of tissueand/or precision of delivery of an ablative fluid, due to the increasedsize (e.g. increased depth) of the target tissue TT including anassociated safety-margin of tissue to which treatment causes nosignificant adverse event (e.g. a submucosal layer expanded prior toneighboring mucosal layer ablation). In the embodiment of FIG. 6, targettissue TT includes one or more tubular tissue segments, such as one ormore axial tissue segments within a body lumen of a mammalian patient.In some embodiments, target tissue TT expanded and/or treated comprisesa continuous segment (e.g. a continuous, full-circumferentially treatedsegment) and/or multiple discontinuous segments (e.g. multiplefull-circumferentially treated segments) of a duodenum, such as a volumeof tissue comprising at least 15% of the duodenal mucosa distal to theampulla of Vater, at least 20% of the duodenal mucosa distal to theampulla of Vater, at least 25% of the duodenal mucosa distal to theampulla of Vater, at least 30% of the duodenal mucosa distal to theampulla of Vater, at least 50% of the duodenal mucosa distal to theampulla of Vater, or at least 67% of the duodenal mucosa distal to theampulla of Vater. The entirety of tissue treated can comprise tissuedistal to the ampulla of Vater, such as in a procedure in which at least50% of post-ampullary duodenal mucosa is treated.

In some embodiments, the target tissue TT comprises a treatment portionincluding duodenal mucosal tissue and a safety-margin portion comprisingat least an innermost layer of the duodenal submucosa (e.g. an innermostlayer of duodenal submucosa expanded by a device of the presentinventive concepts). System 10 can be configured to treat the duodenalmucosa while avoiding damage to duodenal adventitial tissue (e.g.non-target tissue), such as by avoiding damage to: tissue beyond themucosa; tissue beyond the superficial submucosa; and/or tissue beyondthe deep submucosa. In some embodiments, system 10 comprises marker 195,such as marker 195 shown deployed in segment of the GI tract of FIG. 6and described hereabove in reference to FIGS. 1 and 3. Marker 195 can bepositioned or otherwise deployed via endoscope 50, device 100, and/oranother device (e.g. a catheter device) of system 10.

System 10 can include one or more tissue treatment devices such as firsttissue treatment device 100 and second tissue treatment device 100′(singly or collectively, device 100). First device 100 and/or seconddevice 100′ can be further constructed and arranged to expand tissue, asdescribed in detail herein. Alternatively or additionally, system 10 caninclude separate tissue expansion device 20. First device 100 can beused in a first clinical procedure comprising expansion and/or treatmentof target tissue TT, and second device 100′ can be used in a secondclinical procedure comprising expansion and/or treatment of targettissue TT. In some embodiments, the second clinical procedure isperformed at least twenty-four hours after the first clinical procedure.Tissue expansions and/or treatments performed in the second clinicalprocedure can be constructed and arranged based on one or more outcomesof the first clinical procedure. Additional tissue expansion and/ortissue treatment devices can be included in system 10, such as toperform a third or other subsequent clinical procedures including tissueexpansions and/or treatments.

First device 100 and second device 100′ can be similar or dissimilardevices, and can be constructed and arranged to perform similar ordissimilar treatments to similar or dissimilar volumes of tissue.Differences between first device 100 and second device 100′ can includebut are not limited to: type of ablative treatment provided such as typeof energy delivered; type of non-ablative treatment provided; type oftissue treatment assembly; type of tissue treatment element; length ofthe device; diameter of a portion of the device; and combinations ofthese. In some embodiments, first device 100 comprises a first tissuetreatment element constructed and arranged to deliver a different formof energy than a second tissue treatment element of second device 100′.Alternatively or additionally, first device 100 can comprise a firsttissue treatment element with a different geometry (e.g. differentdiameter, length and/or tissue contact surface area or shape), than asecond tissue treatment element of second device 100′.

System 10 can include one or more body introduction devices, such asendoscope 50. Endoscope 50 can comprise a standard GI endoscope such asan endoscope with one or more working channels configured to slidinglyreceive first device 100 (as shown), second device 100′ and/or anotherelongate device of system 10. Additionally or alternatively, system 10can include other body introduction devices, such as a laparoscopicport, vascular introducer, sheath (e.g. a scope attached sheath such assheath 80 of FIG. 1) and/or other introducer.

System 10 includes console 200, which includes user interface 205,controller 210, fluid source 220, vacuum source 230 and inflation source240. Console 200, via ports 201, is operably connected to handle 102 ofdevice 100 via tubes 203 and/or cable 202. User interface 205,controller 210, fluid source 220, vacuum source 230, inflation source240, ports 201 can be of similar construction and arrangement to similarcomponents of device 100 of FIG. 1.

System 10 can include injectate 221, which is delivered to device 100 ordevice 20 by fluid source 220. Injectate 221 can comprise a fluidselected from the group consisting of: water; saline; a fluid with a dyesuch as a visible dye such as indigo carmine; methylene blue; India ink;SPOT™ dye; a gel; a hydrogel; a protein hydrogel; a fluid containing avisualizable media such as a media visualizable under X-ray, ultrasoundimaging and/or magnetic resonance imaging; ethylene vinyl alcohol(EVOH); and combinations of these. In some embodiments, injectate 221can comprise a material constructed and arranged to cause a narrowing orother restriction that results in a therapeutic benefit to the patient,such as is described in applicant's co-pending International PatentApplication Serial Number PCT/US2014/066829, entitled “Systems, Devicesand Methods for the Creation of a Therapeutic Restriction in theGastrointestinal Tract”, filed Nov. 21, 2014, the entire content ofwhich is incorporated herein by reference in its entirety. In theseembodiments, injectate 221 can comprise a material configured to remainin place (e.g. within one or more tissue layers of the GI tract) for anextended period of time, such as at least 1 day, 1 week, 1 month, 3months or 6 months. Injectate 221 can comprise a biopolymer (e.g. EVOH)and/or an adhesive (e.g. cyanoacrylate)

In some embodiments, console 200 comprises an energy delivery unit, EDU250. EDU 250 can be constructed and arranged to deliver ablative fluidsor other ablative energy to one or more components of device 100, suchas an expandable tissue treatment assembly, expandable assembly 130described herebelow, or to a separate tissue treatment device, such asdevice 100′. In some embodiments, console 200 comprises a motion controlmechanism, motion transfer assembly 260. Motion transfer assembly 260can be constructed and arranged to rotate, translate, vibrate and/orotherwise move one or more components of device 100, such as expandableassembly 130 and/or expandable assembly 160, each described in detailherebelow. In some embodiments, motion transfer assembly 260 isconstructed and arranged to rotate another device or component of system10, such as a tissue treatment element or other component of treatmentdevice 100. In some embodiments, motion transfer assembly 260 isconstructed and arranged to steer a shaft of one or more components ofsystem 10, such as one or more shafts 110 of device 100.

Tissue treatment device 100 can comprise one or more shafts 110 (e.g. asingle shaft or multiple columnal shafts) which attach on their proximalend to handle 102. A distal portion of one or more shafts 110 caninclude a radially expandable assembly 160 comprising one or more fluiddelivery elements 168, each attached to a fluid delivery tube 162. Fluiddelivery tubes 162 can travel proximally through one or more shafts 110and into handle 102. Handle 102 can fluidly attach (e.g. via one or moreports and/or via tubes 203) to console 200 such that injectate 221and/or another fluid can be provided to fluid delivery element 168 viafluid source 220. In some embodiments, two fluid delivery elements 168are included (e.g. mounted 180° apart on expandable element 166). Insome embodiments, three fluid delivery elements 168 are included (e.g.mounted 120° apart on expandable element 166). In some embodiments, fouror more fluid delivery elements 168 are included (e.g. four elementsmounted 90° apart on expandable element 166). In some embodiments, threeor more fluid delivery tubes 162 are attached to expandable element 166with spacing to accommodate advancement of endoscope 50 proximate toexpandable element 166. A distal portion of one or more shafts 110further include a tissue treatment assembly, expandable assembly 130 asshown. Expandable assembly 130 can be positioned distal or proximal (asshown) to expandable assembly 160 (i.e. when device 100 is configured toboth treat tissue and expand tissue and includes both expandableassembly 130 for tissue treatment and expandable assembly 160 for tissueexpansion).

Motion transfer assembly 260 can be configured to rotate expandableassembly 130 and/or expandable assembly 160 independently or in unison.Motion transfer assembly 260 can be configured to translate expandableassembly 130 as treatment is applied to a portion of target tissue TT.In some embodiments, contiguous tissue segments are treated by device100 continuously as motion transfer assembly 260 causes expandableassembly 130 to translate at a rate of at least 10 cm/minute, or at arate of least 20 cm/minute. In some embodiments, expandable assembly 130is manually translated, such as at a rate of at least 10 cm/minute, orat least 20 cm/minute. Motion transfer assembly 260 can be configured totranslate expandable assembly 130 between a first tissue treatment and asecond tissue treatment (e.g. between a first segment of duodenal mucosatreated in the first treatment and a second segment of duodenal mucosatreated in the second treatment). Motion transfer assembly 260 caninclude one or more rotational and/or linear drive assemblies, such asthose including rotational motors, magnetic drives, lead screws and/orother linear actuators, and the like which are operably connected toshaft 110 a and/or 110 b. Shafts 110 a and/or 110 b are constructed withsufficient column strength and/or torque transfer properties toadequately rotate and/or translate expandable assembly 130 and/orexpandable assembly 160, respectively. Motion transfer assembly 260 canbe in communication with controller 210, such as to activate, adjustand/or otherwise control motion transfer assembly 260 and thus themotion of expandable assembly 130 and/or expandable assembly 160. Motiontransfer assembly 260 can be manually driven and/or automatically (e.g.motor) driven. Alternatively or additionally, motion transfer assembly260 can be used to advance and/or retract expandable assembly 130 and/orexpandable assembly 160 from a first position to treat a first portionof target tissue, to a second position to treat a second portion oftarget tissue. In these embodiments, repositioning of expandableassembly 130 and/or expandable assembly 160 can be configured to provideoverlapping treatment.

Shafts 110 a and 110 b can include one or more lumens passingtherethrough, and can comprise wires and/or optical fibers for transferof data and/or energy such as RF energy to a functional element. such asfunctional element 139 of expandable assembly 130 and/or functionalelement 169 of expandable assembly 160. Shafts 110 a and/or 110 b cancomprise one or more shafts, such as one or more concentric shaftsconfigured to deliver and/or recirculate hot and/or cold fluid throughexpandable assembly 130 and/or expandable assembly 160. In someembodiments, a heated fluid is used to pre-heat one or more device 100components and/or to deliver a bolus of hot fluid energy, each asdescribed in applicant's co-pending U.S. patent application Ser. No.14/470,503, entitled “Heat Ablation Systems, Devices and Methods for theTreatment of Tissue, filed Aug. 27, 2014, the entire content of which isincorporated herein by reference in its entirety. Device 100 cancomprise multiple tissue treatment assemblies, such as a secondexpandable assembly positioned proximal to the expandable assembly 130and a third expandable assembly positioned distal to expandable assembly130 (e.g. expandable assembly 160 as shown in FIG. 6).

The distal end of shaft 110 (e.g. the distal end of shaft 110 b) cancomprise a bulbous element, bulbous tip 115. In these embodiments,bulbous tip 115 can be sized to fit through a working channel ofendoscope 50, such as when bulbous tip 115 has a diameter less than 6 mmor less than 4 mm. Alternatively, bulbous tip 115 can have a largerdiameter, such as a diameter or other geometry configured to assist insmoothly traversing plicae, such as a diameter of at least 8 mm. In someembodiments, bulbous tip 115 comprises a diameter between 4 mm and 9 mm,such as a diameter between 4 mm and 6 mm. In some embodiments, bulboustip 115 comprises at least a radiopaque portion.

Shafts 110 a and 110 b of FIG. 6 are sized and configured such thatshaft 110 a slidingly receives shaft 110 b, such that they can beadvanced and/or retracted in unison or independently. Differentialmotion between shafts 110 a and 110 b can be used to change the distancebetween expandable assembly 130 and expandable assembly 160. In someembodiments, motion transfer assembly 260 is configured to rotate and/oraxially translate shafts 110 a and/or 110 b such that expandableassembly 130 and/or expandable assembly 160, respectively, are rotatedand/or translated. In some embodiments, device 100 comprises a flexibleportion (e.g. a flexible portion of shafts 110 a and 110 b, such as aflexible distal portion of shaft 110 b) with a diameter less than 6 mm.In some embodiments, the flexible portion is configured to pass througha working channel of an endoscope with a diameter of less than or equalto 6.0 mm, 4.2 mm, 3.8 mm, 3.2 mm or 2.8 mm. In some embodiments, device100 comprises a shaft length of 100 cm or longer, or otherwise comprisesa length sufficient to be orally and/or nasally inserted into a patient,and subsequently advanced to reach the esophagus, stomach, duodenumand/or jejunum; and/or rectally inserted into a patient, andsubsequently advanced to reach the terminal ileum of that patient. InFIG. 6, shafts 110 a and 110 b have been inserted through a workingchannel (e.g. a 6 mm working channel), lumen 51, of endoscope 50,typically a GI endoscope. Shafts 110 a and/or 110 b can be inserted overa standard interventional guidewire, such as guidewire 60 shown exitingthe distal end of shaft 110 b. In an alternative embodiment, shafts 110a and 110 b are positioned in a side-by-side configuration, such as tobe placed in two separate lumens of endoscope 50 or in two othernon-coaxial locations. In some embodiments, one or both of shafts 110 aor 110 b passes through a body lumen or other internal body locationalongside endoscope 50 (i.e. not through lumen 51, traveling relativelyparallel with but external to endoscope 50). Shaft 110 a and/or 110 bcan include a manipulating element constructed and arranged to deflectand/or steer a distal portion of the shaft, such as via one or morehandle 102 controlled and/or motion transfer assembly 260 controlledpull wires that extend and are attached to a distal portion of the shaft(pull wires not shown but well known to those of skill in the art), suchas to deflect and/or steer expandable assembly 130 and/or expandableassembly 160 towards and/or away from tissue and/or assist in navigatingexpandable assembly 130 and/or expandable assembly 160 through tortuousanatomy.

Handle 102 can comprise one or more controls included in user interface105. In some embodiments, user interface 105 comprises one or morecontrols selected from the group consisting of: electrical control;mechanical control; button; knob; switch; lever; touchscreen; andcombinations of these. In some embodiments, a mechanical control isoperably attached to a mechanical assembly, such as a cam or othermechanical advantage mechanism used to transmit a force (e.g. transmitforce to a pull wire). In some embodiments, an electrical control isused to attach one or more components of system 10 to power and/or toactivate an electrically powered mechanical mechanism such as a solenoidor an electronic valve. User interface 105 can be configured to allow anoperator to initiate, regulate, modify, stop and/or otherwise controlone or more functions of console 200 and/or device 100.

In some embodiments, user interface 105 comprises one or more knobs orother controls used to advance and/or retract one or more fluid deliveryelements 168, positioned on expandable element 166 of expandableassembly 160, each described in detail herebelow. In some embodiments,one or more fluid delivery elements 168 are advanced and/or retractedvia a force limiting assembly 140. Force limiting assembly 140 can beconstructed and arranged to allow a single control (e.g. a sliding knob)to advance multiple fluid delivery elements 168 simultaneously. In someembodiments, advancement and/or retraction of one or more fluid deliveryelements 168 is limited by one or more mechanical stops.

In some embodiments, user interface 105 comprises a button, touch screendisplay and/or other control used to initiate, regulate, modify, stopand/or otherwise control one or more parameters of console 200, such asa tissue expanding fluid parameter selected from the group consistingof: flow rate of tissue expanding fluid; duration of tissue expandingfluid flow; volume of tissue expanding fluid; temperature of tissueexpanding fluid; pressure of tissue expanding fluid; a tissue expandingfluid threshold parameter level (e.g. maximum or minimum flow rate,duration, volume, temperature and/or pressure); type of tissue expandingfluid; and combinations thereof. In some embodiments, user interface 105comprises a button, touch screen display and/or other control used toinitiate, regulate, modify, stop and/or otherwise control one or moreparameters of EDU 250, such as an ablation parameter selected from thegroup consisting of: flow rate of ablative fluid; volume of ablativefluid; pressure of ablative fluid; temperature of ablative fluid; typeof energy delivered; type of RF energy delivered (e.g. monopolar,bipolar or both); amount of RF energy delivered (e.g. voltage, currentand/or power delivered); and combinations of these.

Device 100 of FIG. 6 includes an outer shaft 110 a and an inner shaft110 b (generally shaft 110 or shafts 110). Expandable assembly 160 ismounted to shaft 110 b, and expandable assembly 130 is mounted proximalto expandable assembly 160, shown positioned on shaft 110 a. In someembodiments, device 100 comprises a single shaft, and expandableassembly 130 and/or expandable assembly 160 are mounted to that singleshaft. Expandable assembly 160 is constructed and arranged to deliverfluid, via one or more fluid delivery elements 168, into target tissueTT, such as to expand tissue proximate target tissue TT. In someembodiments, expandable assembly 160 can be configured in one or morevarious forms to treat, modify, manipulate, measure and/or diagnosetarget tissue TT and/or other tubular tissue. Expandable assembly 160can comprise one or more expandable elements 166, such as one or moreexpandable elements selected from the group consisting of: an inflatableor otherwise expandable balloon; a radially expandable stent or cage; anarray of splines; one or more radially deployable arms; a spiral orother helical structure; a furlable structure such as a furlable sheet;an unfurlable structure such as an unfurlable sheet; a foldablestructure such as a foldable sheet; an unfoldable structure such as anunfoldable sheet; and combinations of these. In some embodiments,expandable assembly 160 is inflatable (e.g. an inflatable balloon), andinflation fluid can be delivered into expandable assembly 160 via aninflation tube 161. Inflation tube 161 can comprise a lumen of shaft 110b (or a tube within shaft 110 b) that travels proximally through shaft110 b and shaft 110 a, such as to receive inflation fluid delivered byinflation source 240. Expandable assembly 160 can be positioned distalto expandable assembly 130 as shown in FIG. 6, or alternatively,expandable assembly 160 can be positioned proximal to expandableassembly 130, such as when expandable assembly 130 is mounted to shaft110 b and expandable assembly 160 is mounted to shaft 110 a.

Expandable assembly 130 can be radially expandable, similar toexpandable assembly 160 and/or it can include one or more radiallyexpandable elements, such as those described hereabove in reference toexpandable assembly 160 and/or expandable element 166. System 10 can beconfigured to allow expansion of expandable assembly 130 to cause one ormore treatment elements 135 to approach and/or contact a tissue wallsuch as a duodenal wall, such as when one or more treatment elements 135comprise an ablative fluid delivered to a balloon and configured toablate tissue, or when one or more treatment elements 135 comprise anelectrode configured to deliver RF energy to ablate tissue. Expandableassembly 130 can be configured to expand to a diameter less than thediameter of the target tissue TT, such as when a vacuum is applied tocause the target tissue TT diameter to decrease sufficiently to makecontact with expandable assembly 130 and/or one or more treatmentelements 135. System 10 can be configured to allow expansion oftreatment assembly 130 to cause one or more treatment elements 135 to bepositioned at a fixed distance from the luminal wall of tubular tissue,such as a positioning at a fixed distance of at least 250 microns, atleast 500 microns, or at least 1 mm from a tissue wall, such as when oneor more treatment elements 135 are configured to deliver ablative fluidto the target tissue TT and/or to deliver light energy to the targettissue TT. In addition to treating target tissue TT, treatment assembly130 and/or one or more treatment elements 135 can be configured in oneor more various forms to modify, manipulate, measure and/or diagnosetarget tissue TT and/or other tubular or non-tubular tissue. Expansionof treatment assembly 130 can occur prior to, during and/or aftertreatment of target tissue TT by treatment element 135. Treatmentelement 135 can be mounted on, within and/or inside of an expandableassembly, such as on, within and/or inside of an expandable balloon.Treatment assembly 130 can be constructed and arranged to expand andcontact luminal wall tissue without applying an undesired force to theluminal wall tissue, such as by applying a pressure of less than 2.0 psior less than 1.2 psi. Expandable assembly 130 can be constructed andarranged to expand to a diameter between 20 mm and 35 mm, such as to adiameter between 20 mm and 27.5 mm. Expandable assembly 130 can beconstructed and arranged to contact luminal wall tissue with a pressureof at least 0.6 psi.

In some embodiments, expandable element 136 of expandable assembly 130and/or expandable element 166 of expandable assembly 160 compriseinflatable or otherwise expandable balloons, such as one or more of: acompliant balloon; a non-compliant balloon; a balloon with a pressurethreshold; a balloon with compliant and non-compliant portions; aballoon with a fluid entry port; a balloon with a fluid exit port; andcombinations of these. In some embodiments, expandable element 136and/or expandable element 166 comprise a balloon which is fluidlyattached to an inflation tube, such as inflation tube 161 which travelsproximally through shaft 110 a and/or 110 b and is attached to one ormore tubes 203 and/or an inflation port on handle 102.

In some embodiments, expandable assembly 160 is constructed and arrangedto exert no more than a maximum threshold force on tissue, such asluminal wall tissue. The threshold force can comprise a force less than2.0 psi, such as a force less than 1.2 psi. Expandable assembly 160 canbe constructed and arranged to contact luminal wall tissue with a forceof at least 0.6 psi. Expandable assembly 160 can be constructed andarranged to expand to a target diameter, such as a diameter of at least10 mm, at least 15 mm, at least 25 mm, at least 30 mm or at least 40 mm.In some embodiments, expandable assembly 160 is constructed and arrangedto expand to a diameter between 20 mm and 35 mm, such as a diameterbetween 20 mm and 27.5 mm. In some embodiments, expandable assembly 160has its diameter controlled by a component of system 10 (e.g. controller210 and/or inflation source 240), such as to control the diameter to atleast 10 mm, at least 15 mm, at least 20 mm, at least 25 mm, at least 30mm, or at least 40 mm, or to control the diameter to a diameter between20 mm and 35 mm. In some embodiments, expandable assembly 160 isconstructed and arranged to expand to its target diameter in less than60 seconds, such as less than 30 seconds or less than 15 seconds. Insome embodiments, expandable assembly 160 is expanded to a targetdiameter by inflating with fluid delivered at a constant pressure (e.g.approximately 0.7 psi) until the target diameter is reached. In someembodiments, expandable assembly 160 is constructed and arranged toexpand to a diameter less than the diameter of the lumen of the GI tractproximate expandable assembly 160. In these embodiments, vacuum can beapplied (e.g. via an endoscope 50 or device 100 insufflation port),which brings the tissue of the luminal wall toward a tissue capture port167 and/or a fluid delivery element 168.

In some embodiments, expandable assembly 130 is constructed and arrangedto exert no more than a maximum threshold force on tissue, such asluminal wall tissue. Expandable assembly 130 can be constructed andarranged to treat tissue while maintaining a pressure of at least 0.6psi. Expandable assembly 130 can be constructed and arranged to expandto a target diameter, such as a diameter of at least 10 mm, at least 15mm, at least 25 mm, at least 30 mm or at least 40 mm. In someembodiments, expandable assembly 130 is constructed and arranged toexpand to a diameter between 20 mm and 35 mm, such as a diameter between20 mm and 27.5 mm. In some embodiments, expandable assembly 130 has itsdiameter controlled by a component of system 10 (e.g. controller 210,inflation source 240 and/or EDU 250), such as to control the diameter toat least 10 mm, at least 15 mm, at least 20 mm, at least 25 mm, at least30 mm, or at least 40 mm, or to control the diameter to a diameterbetween 20 mm and 35 mm. In some embodiments, expandable assembly 130 isconstructed and arranged to expand to a diameter less than the diameterof the lumen of the GI tract proximate expandable assembly 130. In theseembodiments, vacuum can be applied (e.g. via an endoscope 50 or device100 insufflation port), which brings the tissue of the luminal walltoward expandable assembly 130 and/or treatment element 135.

In some embodiments, expandable assembly 130 and/or expandable assembly160 comprise a length of at least 10 mm, such as a length between 10 mmand 40 mm, a length between 15 mm and 30 mm, or a length between 20 mmand 25 mm. In some embodiments, expandable assembly 130 and/orexpandable assembly 160 comprise a length less than or equal to 15 mm,such as when configured to treat curvilinear portions of the GI tract.Multiple assemblies positioned on shafts 110 a and/or 110 b (e.g.between two and twenty treatments and/or expandable assemblies), such asexpandable assembly 130 and expandable assembly 160, can be separatedalong a shaft by a distance less than or equal to 25 mm, such as adistance less than or equal to 20 mm. This separation distance cancomprise the distance between a distal end of a tissue contactingportion of a first expandable element, and the neighboring proximal endof a tissue contacting portion of a second expandable element. In someembodiments, expandable assembly 130 comprises a length, and theseparation distance between expandable assembly 130 and expandableassembly 160 is less than or equal to the expandable assembly 160length. In these embodiments, expandable assembly 130 can comprise asimilar length to that of expandable assembly 160, such as when bothexpandable assembly 130 and expandable assembly 160 comprise an ablationelement as is described herebelow. Expandable assembly 130 and/orexpandable assembly 160 can be sized, constructed and/or arranged toexpand tissue and/or ablate tissue, or otherwise perform a function,while positioned in a curved segment of the GI tract.

Expandable assembly 130 and/or expandable assembly 160 can beresiliently biased, such as a resilient bias in a radially expanded orradially compacted state. In some embodiments, expandable assembly 130and/or expandable assembly 160 are expanded and/or compacted by acontrol shaft, such as control shaft included in conduit 132 or anotherconduit of device 100 and manipulatable by an operator of system 10and/or by motion transfer assembly 260. Expandable assembly 130 and/orexpandable assembly 160 can be constructed and arranged to achieve around or non-round shape (e.g. a football shape) when expanded.Expandable assembly 130 and/or expandable assembly 160 can approximate atubular shape when expanded, such as a relatively constant diameter orvarying diameter tubular shape. Expandable assembly 130 and/orexpandable assembly 160 can be configured to un-fold to a radiallyexpanded state, or to fold to a radially compacted state.

Expandable assembly 160 and at least one fluid delivery element 168 areconfigured to expand or otherwise modify tissue, such as to expand oneor more layers of tissue. One or more fluid delivery elements 168 cancomprise a needle, fluid jet and/or iontophoretic fluid delivery elementconfigured to deliver injectate 221 into target tissue, such as toexpand submucosal or other tissue of the GI tract. Console 200 cancomprise a reservoir or control means for delivering a pre-determinedamount of injectate 221 to tissue by device 100, such as a volume offluid of at least 1 ml, or a volume of fluid of at least 2 ml, 5 ml, 10ml or 25 ml. Device 100 can be configured to inject fluid into multipleinjection sites (e.g. simultaneously or sequentially), such as a set ofmultiple injection sites selected from the group consisting of: at least3 injection sites along a circumference of tubular tissue, a firstcircumferential injection site separated from a second circumferentialinjection site by approximately 1 cm, or between 0.5 cm to 5 cm, orbetween 1 cm and 3 cm, or between 1 cm and 2 cm; two or more injectionsites that are axially and/or radially spaced; two or more injectionssites that are separated based on the diameter of the tubular tissueinto which they are injected; and combinations of these. Fluid can beinjected with the assistance of one or more vacuum applying elementspositioned on or near fluid delivery elements 168, such as tissuecapture ports 167 shown. Tissue capture ports 167 can be of similarconstruction and arrangement to tissue capture ports 47 of FIG. 1described hereabove. Tissue capture ports 167 are configured to applynegative pressure proximate the injection site, such as to capturetissue within the port and avoid the fluid delivery element 168 fromhaving to radially exit tissue capture port 167 to penetrate the tissue.Tissue capture ports 167 can comprise one or more portions that areradiopaque. Console 200 and/or tissue capture ports 167 can beconfigured to discharge or otherwise release tissue from tissue captureport 167, such as by applying a positive pressure to tissue capture port167. Device 100 can comprise one or more sensors configured to monitorthe vacuum level in tissue capture port 167 and/or a fluidly connectinglumen.

As described hereabove, system 10 can be constructed and arranged toboth expand tissue and treat tissue. In some embodiments, one or moredevices 100 can be constructed and arranged to both expand tissue andtreat tissue, such as via a tissue treatment assembly, expandableassembly 130. Alternatively or additionally, system 10 can comprise aseparate device for tissue treatment, tissue treatment device 100′.Device 100′ can comprise one or more tissue treatment elementsconfigured to treat target tissue TT, such as a tissue treatmentassembly similar to expandable assembly 130 described herein. Console200 can further include an energy delivery unit, EDU 250, which can beoperably attached to first device 100 (as shown), tissue second tissuetreatment device 100′ and/or tissue expansion device 20. EDU 250 can beconfigured to provide numerous forms of energy to one or more treatmentelements of device 100 and/or device 100′, such as an energy formselected from the group consisting of: RF energy; microwave energy;laser energy; sound energy such as subsonic sound energy or ultrasoundenergy; chemical energy; thermal energy such as heat energy or cryogenicenergy provided by an ablative fluid; and combinations of these.

In some embodiments, system 10, device 100 and/or device 100′ (singly orcollectively device 100) can be constructed and arranged as is describedin applicant's co-pending U.S. patent application Ser. No. 13/945,138,entitled “Devices and Methods for the Treatment of Tissue”, filed Jul.18, 2013, the entire content of which is incorporated herein byreference in its entirety. In some embodiments, device 100 can beconstructed and arranged to ablate tissue with an ablation treatmentselected from the group consisting of: delivery of thermal energy from aballoon filled with fluid at an ablative temperature; RF energy ablationsuch as monopolar and/or bipolar RF energy ablation; delivery of anablative fluid directly to tissue; cryoablation; delivery of laserenergy; delivery of sound energy such as subsonic sound energy orultrasonic sound energy; plasma energy delivery; argon plasmacoagulation; microwave energy delivery; delivery of non-laser lightenergy; and combinations of these. In some embodiments, device 100 canbe constructed and arranged to perform a non-ablative treatment oftarget tissue, such as with a non-ablative treatment selected from thegroup consisting of: mechanical removal of mucosal tissue; chemical,sclerosant or pharmaceutical injection into the submucosa; radioactiveseed deposition; chemical spray such as an acid spray; pharmacologicadministration such as drug delivery via an agent-eluting balloon; andcombinations of these. Device 100 can be constructed and arranged toresect tissue, such as to resect tissue selected from the groupconsisting of: plicae tissue; mucosal tissue; submucosal tissue; andcombinations of these.

One or more components of console 200 can include a pump and/orreservoir which can provide and/or remove one or more fluids to and/orfrom one or more devices of system 10, such as device 100, device 20and/or endoscope 50. Fluids can be provided (e.g. by EDU 250) tothermally prime (e.g. hot or cold priming) one or more components ofsystem 10, as described in detail herebelow. Tissue ablating fluids canbe provided, such as hot or cold ablative fluids provided by EDU 250 toexpandable assembly 130 of device 100. Tissue neutralizing fluids can beprovided (e.g. by EDU 250) such as cooling fluids provided afterelevated temperature ablation, warming fluids provided after cryogenicablation and/or chemically neutralizing fluids delivered to neutralize achemical agent. Fluids can be provided (e.g. a gas) to insufflate aportion of the GI tract, such as fluids provided through a lumen ofendoscope 50 or a lumen of device 100. Console 200 can include one ormore fluid reservoirs (e.g. one or more reservoirs included in fluidsource 220, vacuum source 230, inflation source 240 and/or energydelivery unit 250) constructed and arranged to supply or receive fluidsto and/or from device 100. In some embodiments, console 200 includes oneor more reservoirs, one or more pumps, and one or more cooling orheating units such that console 200 recirculates or otherwisecontinuously provides one or more hot and/or cold fluids through adevice of system 10, such as to recirculate fluid through one or moreportions of device 100, device 20 and/or endoscope 50.

Expandable assembly 130 can include one or more elements constructed andarranged to ablate or otherwise treat target tissue TT, such as tissuetreatment element 135 shown. Treatment element 135 can comprise one ormore elements selected from the group consisting of: a bolus of ablativefluid; recirculating ablative fluid; continuously replenished ablativefluid; an electrical energy delivery element such as one or moreelectrodes constructed and arranged to deliver RF energy; a fluiddelivery element such as a nozzle or permeable surface constructed andarranged to deliver ablative fluid directly in contact with targettissue TT; a balloon such as a balloon constructed and arranged toreceive a bolus of ablative fluid and deliver hot or cold thermal energyto ablate target tissue TT; a balloon such as a balloon constructed andarranged to receive a recirculating ablative fluid and deliver hot orcold thermal energy to ablate target tissue TT; a laser energy deliveryelement such as an optical fiber, a focusing lens and/or other opticalcomponent; a sound energy delivery element such as a piezo-based elementconfigured to deliver ultrasonic and/or subsonic energy; a tissueabrading element; and combinations of these. Treatment element 135 canbe positioned on, in, within and/or passing through one or morecomponents of expandable assembly 130, such as a balloon, cage, splineor other component as are described herein. Expandable assembly 130and/or treatment element 135 can comprise an energy distributionelement, such as one or more optical components configured to rotate,translate and/or otherwise distribute laser or other light energy totarget tissue. In some embodiments, expandable assembly 130 and/ortreatment element 135 comprise an energy distribution element includinga rotating element such a rotating mirror; a rotating prism and/or arotating diffractive optic. In some embodiments, device 100 comprisesone or more fibers that deliver laser or other light energy to atreatment element 135 when expandable assembly 130 comprises a balloonfilled with light-scattering material.

In some embodiments, device 100 delivers thermal (e.g. heat orcryogenic) energy to tissue, such as when expandable assembly 130 and/ortreatment element 135 comprises an ablative fluid delivered to aballoon, and the ablative fluid comprises a hot or cold volume of fluidat a temperature sufficient to ablate tissue when the balloon contactsthe tissue. The hot or cold volume of fluid can be provided toexpandable assembly 130 via EDU 250. System 10 can be configured todeliver thermal energy to tissue as is described in applicant'sco-pending U.S. patent application Ser. No. 14/470,503, entitled “HeatAblation Systems, Devices and Methods for the Treatment of Tissue, filedAug. 27, 2014, or as is described in applicant's co-pendingInternational Patent Application Serial Number PCT/US2014/055514,entitled “Systems, Methods and Devices for Treatment of Target Tissue”,filed Sep. 12, 2014, the entire contents of each of which isincorporated herein by reference in their entirety.

In some embodiments, device 100 delivers RF energy to tissue, such aswhen treatment element 135 comprises one or more electrodes constructedand arranged to receive RF energy provided by EDU 250. In theseembodiments, the one or more electrodes can comprise one or moreconductive dots or other conductive elements positioned on an expandableelement such as a balloon. In some embodiments, EDU 250 is configured todeliver RF energy to one or more electrodes of device 100, such as in amonopolar mode through a grounding pad such as ground pad 70 and/or in abipolar mode between two or more electrodes of device 100. System 10 canbe configured to deliver RF energy to tissue as is described inapplicant's co-pending U.S. patent application Ser. No. 14/609,332,entitled “Electrical Energy Ablation Systems, Devices and Methods forthe Treatment of Tissue”, filed Jan. 29, 2015, the entire content ofwhich is incorporated herein by reference in its entirety.

In some embodiments, device 100 delivers ablative fluid directly totissue, such as when treatment element 135 comprises one or more nozzlesor other ablative fluid delivery elements. In these embodiments,treatment element 135 can be constructed and arranged to ablate targettissue TT by delivering ablative fluid provided by EDU 250. Treatmentelement 135 can include one or more fluid delivery elements selectedfrom the group consisting of: nozzle such as a nozzle configured todeliver a cone or other shaped spray of fluid; needle; opening; hole;slit; permeable membrane; misting element; vaporizer; and combinationsof these. Treatment element 135 can comprise the fluid delivery elementand/or the ablative fluid. Ablative fluid can comprise one or moreliquids or gases that are delivered to target tissue TT at a temperatureabove or below a threshold that would ablate tissue. In someembodiments, the ablative fluid delivered by treatment element 135comprises steam, such as steam at a temperature of 100° C. or above. Insome embodiments, the ablative fluid delivered by treatment element 135comprises a vaporized fluid at a temperature below 100° C., such as avaporized fluid at a temperature between 70° C. and 90° C. In someembodiments, the ablative fluid delivered by treatment element 135comprises a gas, such as a gas between 60° C. and 99° C., such as a gasdelivered to tissue at a temperature between 70° C. and 90° C. In someembodiments, the ablative fluid delivered by treatment element 135comprises a vaporized liquid, such as a vaporized liquid delivered totissue at a temperature below 100° C., such as at a temperature between70° C. and 90° C. Alternatively or additionally, an ablative fluiddelivered by treatment element 135 can comprise one or more liquids orgases that cause tissue necrosis or otherwise treat target tissue TTusing one or more chemically active agents (e.g. ablation not primarilycaused by delivery or removal of heat from tissue). In theseembodiments, the agent can comprise an agent selected from the groupconsisting of: sclerotic agent; acid; base; saline; alcohol; carbondioxide; nitrous oxide; nitrogen; acetic acid; glycerol; andcombinations of these. In these embodiments, a counter-actingneutralizing agent can be included, such as a neutralizing agentdelivered by device 100 or another device or component of system 10 thatis used to neutralize, impede, reduce and/or limit tissue ablationcaused by the delivery of a necrotic agent-based ablative fluid. Thecounter-acting agent can be delivered by treatment element 135 and/oranother component of device 100 or system 10. The neutralizing agent cancomprise an agent selected from the group consisting of: anti-scleroticagent; base; acid; buffer solution; saline; water; and combinations ofthese. System 10 can be configured to deliver ablative fluid directly totissue as is described in applicant's co-pending U.S. patent applicationSer. No. 14/609,334, entitled “Ablation Systems, Devices and Methods forthe Treatment of Tissue”, filed Jan. 29, 2015, the entire content ofwhich is incorporated herein by reference in its entirety.

Expandable assembly 130 can be positioned on shaft 110 a as shown.Treatment element 135 is electrically, fluidly, mechanically and/orotherwise operably connected to conduit 132. Conduit 132 can compriseone or more elongate filaments selected from the group consisting of: awire such as one or more wires configured to deliver electrical or otherpower and/or transmit electrical or other data signals; an optical fibersuch as one or more optical fibers configured to deliver power and/ortransmit data signals; a tube such as a fluid delivery or a vacuumsupplying tube; a lumen such as a fluid delivery lumen or a vacuumsupplying lumen; a control rod such as an advanceable and/or retractablecontrol rod; and combinations of these. Conduit 132 travels proximallythrough shaft 110 a and operably attaches to console 200 (e.g. via oneor more ports 201), such as to operably attach to one or more of: fluidsource 220; vacuum source 230; inflation source 240; EDU 250; motiontransfer assembly 260; and/or combinations of these, and/or to attach toanother component, assembly or device of system 10. In some embodiments,one or more portions (e.g. one or more filaments) of conduit 132 extendto expandable assembly, such as one or more filaments selected from thegroup consisting of: a control rod; an inflation tube; an inflationlumen; a fluid delivery tube; a wire; an optical fiber; and combinationsof these.

In some embodiments, conduit 132 comprises one or more fluid deliverytubes and/or lumens constructed and arranged to deliver and/orrecirculate heated or chilled fluid into expandable assembly 130, suchas heated or chilled fluid received from EDU 250 and delivered intotreatment element 135, such as when treatment element 135 comprisesablative fluid and/or a balloon or other fluid reservoir receiving theablative fluid, where the ablative fluid is at a temperature sufficientto ablate tissue when expandable assembly 130 contacts the tissue.Alternatively or additionally, conduit 132 can comprise one or morefluid delivery tubes constructed and arranged to deliver an ablativefluid to expandable assembly 130, such as ablative fluid provided by EDU250 and delivered directly to target tissue TT by one or more treatmentelements 135, such as when treatment element 135 comprises a fluiddelivery element such as a nozzle. Conduit 132 can further comprise oneor more insulating layers configured to prevent transfer of heat intoand/or out of conduit 132. Conduit 132 can include a surrounding lumenwhich receives a circulating fluid configured to provide an insulating,warming and/or cooling effect on conduit 132 and/or any fluid containedwithin conduit 132. Conduit 132 and/or another fluid delivery tube ofsystem 10 can comprise one or more elongate hollow tubes, such as ahollow tube positioned within shaft 110 a. Alternatively, conduit 132and/or another fluid delivery tube of system 10 can comprise a lumenwithin a shaft, such as a lumen within shaft 110 a. In some embodiments,conduit 132 and/or another fluid delivery tube of system 10 comprisesboth a lumen and a hollow tube, such as when the lumen and hollow tubeare fluidly connected in an end-to-end configuration. Conduit 132typically attaches to console 200 with one or more operator attachablefluid connection ports (e.g. attaching to tubes 203), such as a fluidconnection port included in handle 102 positioned on the proximal end ofshaft 110 a. Conduit 132 can comprise one or more fluid delivery tubesincluding one or more valves, not shown but such as a duck-bill or othervalve used to regulate flow within conduit 132, such as to regulate flowpressure and/or direction.

In some embodiments, conduit 132 comprises one or more elongatefilaments constructed and arranged to transmit energy and/or data.Conduit 132 can comprise one or more wires constructed and arranged todeliver RF energy to one or more electrode-type treatment elements 135,such as when the treatment elements 135 are configured to ablate targettissue TT in monopolar and/or bipolar modes as described herein. Conduit132 can comprise one or more filaments constructed and arranged todeliver laser energy, such as one or more optical fibers constructed andarranged to deliver laser energy to one or more lenses or other opticalcomponent-type treatment elements 135, such as to ablate target tissueTT with laser or other light energy. Conduit 132 can comprise one ormore wires or other energy transfer filaments constructed and arrangedto allow a sound producing-type treatment element to ablate targettissue TT with sound energy such as ultrasonic or subsonic sound energy.Conduit 132 can comprise one or more wires or optical fibers configuredto transmit information, such as information received from a sensor ofsystem 10 as described herebelow.

In some embodiments, conduit 132 and/or shaft 110 comprises one or morecontrol rods constructed and arranged to cause one or more treatmentelements 135 and/or fluid delivery elements 168 to rotate and/ortranslate, such as when conduit 132 is operably attached to motiontransfer assembly 260, such as prior to, during and/or after expansionof a tissue layer and/or delivery of energy to target tissue. In someembodiments, one or more treatment elements 135 comprise a surfaceconfigured to abrade or otherwise disrupt tissue as it is rotated and/ortranslated by movement of conduit 132. Alternatively or additionally,one or more fluid delivery elements 168 and/or treatment elements 135can deliver energy and/or fluid to tissue, and movement of one or morecontrol rod of conduit 132 and/or shaft 110 changes the location of thetissue segment receiving the energy and/or fluid. Motion of one or morefluid delivery elements 168 and/or treatment elements 135 can beconfigured to expand and/or treat a full circumferential (i.e. 360°)segment of tubular tissue, or a partial circumferential (e.g. 45°-350°)segment of tubular tissue. Motion of one or more treatment elements 135and/or fluid delivery elements 168 can be configured to expand and/ortreat a particular axial length of tubular tissue, such as an axiallength comprising at least 15% of the axial length of the duodenumdistal to the ampulla of Vater, or at least 20% of the axial length ofthe duodenum distal to the ampulla of Vater, or at least 25% of theaxial length of the duodenum distal to the ampulla of Vater, or at least30% of the axial length of the duodenum distal to the ampulla of Vater;or at least 50% of the axial length of the duodenum distal to theampulla of Vater. In some embodiments, only tissue distal to the ampullaof Vater is expanded and/or treated, as has been described in detailhereabove.

EDU 250 can comprise multiple heat or cold sources used to modify thetemperature of one or more fluids provided by and/or passing through EDU250, console 200, device 100 and/or device 20. The heat or cold sourcescan be at a fixed temperature or they can be variable. In someembodiments, a first heat or cold source is at a fixed temperature and asecond heat or cold source is at a variable temperature.

In some embodiments, a cooling fluid is delivered, prior to, duringand/or after a heat ablation treatment of target tissue TT, such as toprecisely control target tissue ablation and avoid ablation ofnon-target tissue. The cooling fluid can be provided by EDU 250 oranother component of console 200, and it can be delivered to tissue,such as target or non-target tissue, and/or it can be delivered to acomponent of system 10 such as to reduce the temperature of a componentof treatment assembly 160 or a component of device 500. Expandableassembly 130, expandable assembly 160, treatment element 135, fluiddelivery element 168 and/or another component of system 10 can beconstructed and arranged to deliver the cooling fluid to one or moretissue surfaces, such as a cooling fluid delivered to expandableassembly 130 via conduit 132 and/or a separate inflation tube or lumen(e.g. inflation tube 131 shown) and configured to reduce the temperatureof one or more volumes of tissue (e.g. a cooling step performed prior toa hot fluid ablation step and/or a cooling step performed subsequent toa hot fluid ablation step). In some embodiments, system 10 is configuredto deliver fluid at a sufficiently high temperature to ablate targettissue TT, after which a cooling fluid is automatically and/orsemi-automatically delivered to remove thermal energy from target tissueTT and/or other tissue, such as cooling fluid delivered for a timeperiod of at least 2 seconds, at least 5 seconds, at least 10 seconds orat least 20 seconds. In these embodiments, a cooling step can beperformed prior to the heat ablation step, such as is describedhereabove in reference to FIG. 2.

Ablation provided by system 10 can comprise a non-desiccating or adesiccating ablation. In some embodiments, a non-desiccating ablation isperformed for a first portion of target tissue TT such as in a firsttissue treatment, and a desiccating ablation is performed for a secondportion of target tissue TT such as in a second tissue treatment.Non-desiccating ablations can be performed to treat over-lappingportions of target tissue TT, and/or to avoid creation of tissue debrisif desired. Desiccating ablations can be performed to achieve a higherthermal gradient, to remove excess tissue, and/or to ablate rapidly ifdesired. Console 200, treatment element 135 and/or other components ofsystem 10 can be configured to treat target tissue TT with anon-desiccating ablation, such as by avoiding tissue temperatures above100° C., avoiding the creation of steam, or otherwise avoidingdeleterious desiccation of tissue. System 10 can be configured tominimize heat production in the outermost 50% of a mucosal layer, suchas to ablate the outermost 50% of the mucosal layer via thermalconduction. System 10 can be configured to minimize heat production inthe outermost 80% of a mucosal layer, such as to ablate the outermost80% of the mucosal layer via thermal conduction. System 10 can beconfigured to maximize the flow of electrical current, such as throughthe innermost 50% of a mucosal layer, or through the innermost 20% of amucosal layer. In some embodiments, system 10 can be configured to avoiddetachment of tissue particles.

EDU 250 can be configured to deliver a hot or cold fluid to thermallyprime (i.e. pre-heat or pre-chill, respectively) one or more componentsof system 10. In some embodiments, the one or more components include:conduit 132; a fluid delivery tube such as a tube within shaft 110 a(e.g. inflation tube 131); a fluid delivery lumen such as a lumen withinshaft 110 a and/or shaft 110 b; shaft 110 a; shaft 110 b; fluid deliveryelement 168; treatment element 135; and combinations of these. System 10can be configured to thermally prime one or more components bycirculating or recirculating hot fluid (pre-heat) or cold fluid(pre-chill), such as a hot or cold liquid or gas. In some embodiments,expandable assembly 130 contains and/or treatment element 135 delivers ahot fluid, and one or more components of system 10 are pre-treated witha hot gas. Alternatively or additionally, system 10 can comprise one ormore insulators surrounding one or more conduits, lumens and/or shaftsof device 100 and/or system 10, such as an insulator surrounding conduit132 and/or tube 131 and configured to prevent transfer of heat across(e.g. into or out of) conduit 132 and/or tube 131.

Console 200, treatment element 135 and/or other components of system 10can be configured to treat target tissue TT such that the temperature ofat least a portion of the target tissue TT rises rapidly, such as at arate of greater than or equal to 17.5° C. per second. Treatment can bedelivered to cause the temperature of at least a portion of the targettissue TT to reach a setpoint temperature between 60° C. and 90° C.,such as a setpoint temperature between 65° C. and 85° C. System 10 canbe configured to cause the target tissue TT to elevate to a setpointtemperature and maintain that setpoint temperature, such as bymaintaining the setpoint temperature for a time period between 2 and 40seconds. In these embodiments, the setpoint temperature can be between60° C. and 90° C., such as a setpoint temperature between 65° C. and 85°C. that is maintained for between 5 and 15 seconds. In some embodiments,after a setpoint temperature is achieved and/or maintained, thetreatment can be adjusted (e.g. by adjusting energy delivery from EDU250) such that tissue temperature decreases over time, such as to matcha tissue response of the target tissue TT.

System 10 can be configured to maintain target tissue TT or other tissueunder a threshold (e.g. below a maximum temperature of a heat ablationor above a minimum temperature of a cryogenic ablation) and/or within atemperature range, such as in a closed-loop configuration through theuse of one or more sensors such as functional element 139 of expandableassembly 130 or functional element 169 of expandable assembly 160, eachdescribed in detail herebelow. In some embodiments, tissue temperatureis maintained below 100° C., such as between 60° C. and 90° C., such asbetween 65° C. and 85° C. In some embodiments, system 10 is configuredto maintain the temperature of target tissue TT at a setpointtemperature. The setpoint temperature can vary over time. System 10 canbe configured to deliver energy at a level that increases and/ordecreases over time. In some embodiments, treatment element 135 isconstructed and arranged to cause the temperature of at least a portionof target tissue TT to rapidly rise to a setpoint (e.g. a setpointbetween 60° C. and 75° C.). After the target tissue TT reaches thesetpoint temperature, system 10 can deliver energy or otherwise treatthe target tissue TT to maintain the setpoint temperature for anextended time period.

In some embodiments, EDU 250 is configured to heat or chill one or morefluids, such as one or more ablative fluids provided by EDU 250, orother fluids. In some embodiments, expandable assembly 130 is configuredto heat or chill one or more fluids, such as when functional element 139comprises a heating and/or cooling element. Applicable heating andcooling elements include but are not limited to heat exchangers, heatingcoils, peltier components, refrigeration assemblies, gas expansioncoolers, and the like. Heating and cooling can be applied to a source offluid (e.g. a reservoir of console 200), or to fluid that is withdrawnfrom device 100 (e.g. a recirculating fluid and/or a body extractedfluid such as recovered, previously delivered, ablative or insufflatingfluid). EDU 250 can include one or more pumps configured to deliverand/or extract fluid at a particular flow rate, pressure, or other fluiddelivery parameter.

Expandable assembly 130 and/or expandable assembly 160 can be configuredto seal a body lumen location, such as to create a full or partialocclusive barrier at a location within the duodenum or other location inthe GI tract. System 10 can be configured to cause a fluid or other sealcomprising an occlusive barrier selected from the group consisting of: apressure seal; a cryogenically applied seal such as an ice ball seal; avacuum seal; a full circumferential seal; a partial circumferentialseal; and combinations of these. In some embodiments, treatment element135 treats a portion of target tissue TT located proximal or distal tothe occlusive barrier. System 10 can include multiple expandableassemblies configured to seal a body lumen location, such as firstexpandable assembly which provides a seal at a proximal end of a segmentof tubular tissue, and a second expandable assembly which provides aseal at a distal end of the tubular tissue segment. In some embodiments,treatment element 135 treats a portion of target tissue TT locatedbetween the two sealed locations, such as between two locations of theduodenum, each duodenal location sealed by an expandable component orassembly of device 100. One or more expandable assemblies can beconfigured to occlude a first location of a body lumen, followed bysubsequent occlusions of one or more different locations within the bodylumen. System 10 can be configured to apply a vacuum between twoocclusive elements, such as a vacuum applied by one or more treatmentelements 135, via one or more functional elements 139 of expandableassembly 130 and/or functional element 169 of expandable assembly 160,and/or by another device or component of system 10. Applied vacuum canbe used to modify (e.g. change the shape of) the tubular tissue betweenthe two occlusive elements and/or to increase the sealing force and/orthe circumferentiality of the seal. In some embodiments, system 10 isconfigured to deploy a detached-balloon configured to occlude a bodylumen, where the detached-balloon can later be punctured or otherwisedeflated for physiologic removal by the GI tract (e.g. similar toocclusive element 193 of FIGS. 5 and 5A-5E). Deployed balloons or otherocclusive elements of system 10 can be positioned to protect tissue,such as to protect the ampulla of Vater and/or the pylorus from adverseeffects that can be caused by treatment of target tissue TT by treatmentelement 135.

Expandable assembly 130 can comprise at least one functional element139, and expandable assembly 160 can comprise at least one functionalelement 169, each as shown. Functional elements 139 and/or 169 can beelements selected from the group consisting of: a sensor; a transducer;an ablation element such as one or more electrodes configured to deliverelectrical energy such as radiofrequency (RF) energy; a fluid deliveryelement such as a needle, a fluid jet, a permeable membrane and/or anexit port; a heating element; a cooling element; and combinations ofthese.

In some embodiments, expandable assembly 160 is configured to ablatetissue, such as via functional element 169. Functional element 169 ofexpandable assembly 160 can comprise one or more ablation elements, suchas those described herein. In some embodiments, functional element 169comprises an ablation element selected from the group consisting of: anRF energy delivery element such as one or more electrodes, eachcomprising one or more elongate conductors; an ultrasonic transducersuch as one or more piezo crystals configured to ablate tissue; a laserenergy delivery element such as one or more optical fibers and/or laserdiodes; a heat delivery element such as a hot fluid filled balloon; arotating ablation element; a circumferential array of ablation elements;and combinations of these. In these embodiments, either or bothexpandable assembly 130 and expandable assembly 160 can be used toablate target tissue TT. EDU 250 or another component of system 10 canbe configured to deliver RF or other energy to any functional element139 and/or 169. System 10 can include ground pad 70, such as a standardRF energy delivery ground pad typically placed on the patient's back,such that EDU 250 can supply RF energy to a functional element 139and/or 169 and/or any other electrodes of system 10 in monopolar,bipolar and/or combined monopolar-bipolar energy delivery modes.

In some embodiments, functional element 139 of expandable assembly 130and/or functional element 169 of expandable assembly 160 comprises anabrasive element configured for abrading target tissue, such as anabrasive element attached to a balloon or expandable cage.

In some embodiments, expandable assembly 160 is further configured toperform at least one non-tissue expanding function. In some embodiments,expandable assembly 160 is configured to ablate tissue, as describedhereabove. Alternatively or additionally, expandable assembly 160 and/orexpandable assembly 130 can be configured to occlude or partiallyocclude a lumen surrounded by tissue (as described hereabove), such as alumen of the GI tract to be occluded during an insufflation procedure,also as described hereabove. Expandable assembly 130 and/or expandableassembly 160 can be configured to manipulate tissue, such as tolinearize and/or distend GI tissue by frictionally engaging (e.g. whenexpanded) and applying forces to the tissue (e.g. by advancing and/orretracting shaft 110 a and/or 110 b). In some embodiments, one or moreexpandable assemblies 130 and/or expandable assemblies 160 can perform afunction selected from the group consisting of: linearizing curvilineartissue; distending tissue; expanding tissue; occluding a body lumen; andcombinations of these. Expandable assembly 130 and/or expandableassembly 160 can be configured to test and/or diagnose tissue, such aswhen expandable assembly 130 and/or expandable assembly 160 is used tomeasure a diameter of tubular tissue into which it has been inserted.Diameter measurements can be performed in various ways, including butnot limited to: injection of a radiopaque fluid into expandable assembly130 and/or expandable assembly 160 and fluoroscopic measurement of theinjected fluid; controlled inflation of expandable assembly 130 and/orexpandable assembly 160 to a pressure whose level corresponds to aluminal diameter; and combinations of these. In some embodiments, device100 includes an expandable assembly that can be expanded with one ormore control rods (e.g. one or more control rods of conduit 132), suchas to perform a diametric measurement of tubular tissue by precisionmeasurement of control rod advancement (e.g. when control rod positioncorrelates to expandable assembly diameter). Alternatively oradditionally, tubular tissue diameter can be determined by measuring thediameter of an expandable assembly when it initially, circumferentiallycontacts the wall of tubular tissue (e.g. when a specific radial forceis achieved and/or when contact is observed such as using fluoroscopy orultrasound visualization devices). In some embodiments, system 10includes a separate device used to perform a diameter measurement, suchas sizing device 30 shown. Sizing device 30 can be of similarconstruction and arrangement to device 30 described hereabove inreference to FIG. 1. One or more energy delivery or other ablationparameters can be adjusted based on the measured diameter of targettissue TT and/or a target tissue segment.

Treatment element 135 can be configured to treat various thicknesses ofGI tissue, such as at least the innermost 500 microns of duodenaltissue, or at least the innermost 1 mm of duodenal tissue. In someembodiments, treatment element 135 can be configured to ablate orotherwise treat a thickness of at least 600 microns, at least 1 mm or atleast 1.25 mm, such as when treating the mucosa of the stomach.Treatment element 135 can be configured to treat a volume of tissuecomprising a surface area and a depth, where the ratio of magnitude ofthe depth to the magnitude of the surface area is less than or equal to1 to 100 (e.g. less than 1%), or less than or equal to 1 to 1000 (e.g.less than 0.1%). In some embodiments, expandable assembly 130 and/orexpandable assembly 160 are configured to be in a relatively rigidstate, such as during treatment of target tissue TT.

Treatment element 135 and/or other treatment elements of the presentinventive concepts can be arranged in an array of elements, such as acircumferential or linear array of elements. The circumferential arraycan comprise a partial circumferential array of treatment elements 135,such as an array covering approximately 45° to 300° of circumferentialarea. Partial circumferential arrays of treatment elements 135 can treata first target tissue segment and a second target tissue segment in twosequential steps, where the array is rotated between treatments (e.g.energy deliveries). The circumferential array can comprise a full 360°array of treatment elements 135, such that a full circumferential volumeof target tissue TT can be treated in single or multiple treatments(e.g. energy deliveries) that do not require repositioning of expandableassembly 130. In some embodiments, less than 360° of tubular tissue istreated, such as by treating a circumferential portion of tissuecomprising less than or equal to a 350°, or between 300° and 350°, suchas to prevent a full circumferential scar from being created.

Two or more treatment elements 135 can be arranged in a helical array.In some embodiments, at least three, four or five treatment elements 135independently treat target tissue, in similar or dissimilar treatments(e.g. similar or dissimilar amounts of energy, provided simultaneouslyand/or sequentially by EDU 250).

In some embodiments, console 200, EDU 250 and/or another device orcomponent of system 10 provides electrical or other energy to acomponent of device 100, such as electrical energy provided to a heatingcoil in a distal portion of device 100, now shown but typicallyconnected to one or more wires of conduit 132 that travel proximallythrough shaft 110 a to handle 102. Console 200, EDU 250 and/or anotherdevice or component of system 10 can provide energy such as electricalenergy to one or more functional elements 139 and/or 169 such as when afunctional element 139 and/or 169 comprises a transducer or otherpowered component.

In some embodiments, treatment element 135 comprises one or moretreatment elements that are constructed and arranged to treat the entireamount of tissue to be treated (“desired treatment area”) with a singleenergy delivery and/or at least without having to reposition device 100.In these embodiments, treatment element 135 can comprise an array oftreatment elements positioned along substantially the entire desiredtreatment area of the target tissue, or treatment element 135 cancomprise one or more treatment elements configured to rotate and/ortranslate along substantially the entire desired treatment area oftissue. Treatment element 135 and/or other tissue treatment elements ofthe present inventive concepts can be configured to treat at least 25%of the desired treatment area of the duodenum simultaneously and/orwithout having to reposition device 100. Alternatively, treatmentelement 135 and/or other ablation elements of the present inventiveconcepts can be configured to treat a first portion of the desiredtreatment area followed by a second portion of the desired treatmentarea. The first and second treated tissue segments can be overlappingand they can have non-parallel central axes (e.g. tissue segments in acurved portion of the duodenum). Three or more target tissue segmentscan be treated, such as to cumulatively ablate at least 10% or at least25% of the duodenal mucosa (e.g. at least 10% or 25% of the duodenalmucosa distal to the ampulla of Vater).

System 10 can be configured to ablate or otherwise treat target tissueTT, such as duodenal mucosal tissue, while avoiding damaging non-targettissue, such as the GI adventitia. Target tissue TT can include at leasta portion of safety-margin tissue comprising tissue whose ablationcauses minimal or no adverse effect to the patient, such as sub-mucosaltissue of the GI tract. Target tissue TT can comprise one or moreportions of tissue that are treated simultaneously or sequentially. Insome embodiments, the target tissue TT comprises at least 10% or atleast 25% of the duodenal mucosa distal to the ampulla of Vater. In someembodiments, the target tissue TT includes the full mucosal thickness ofat least a portion of duodenal tissue, as well as at least the innermost100 microns of submucosal duodenal tissue, or at least the innermost 200microns of submucosal duodenal tissue. The target tissue TT can includeat least one of ileal mucosal tissue or gastric mucosal tissue.

Endoscope 50 can be a standard endoscope, such as a standard GIendoscope, or a customized endoscope, such as an endoscope includingsensor 53 configured to provide information related to the tissueexpansion and/or tissue treatment of the present inventive concepts.Endoscope 50 can include camera 52, such as a visible light, ultrasoundand/or other visualization device used by the operator of system 10prior to, during and/or after the expansion and/or treatment of targettissue TT, such as during insertion and/or removal of endoscope 50and/or shafts 110 a and 110 b of device 100. Camera 52 can providedirect visualization of internal body spaces and tissue, such as theinternal organs of the GI tract. Endoscope 50 can be coupled with orotherwise include a guidewire, e.g. guidewire 60, such as to allowinsertion of endoscope 50 into the jejunum and/or advancement of device100. Device 100 can be constructed and arranged such that endoscope 50can be advanced within 5 cm of expandable assembly 130 and/or expandableassembly 160.

System 10 can be constructed and arranged to perform insufflation of abody lumen, such as insufflation of a segment of the GI tract. The bodylumen can be pressurized, such as by using one or more standardinsufflation techniques. Insufflation fluid can be introduced throughsecond lumen 54 of endoscope 50. Second lumen 54 travels proximally andconnects to a source of insufflation liquid and/or gas, such as console200, and typically a source of air, carbon dioxide, water and/or saline.Alternatively or additionally, insufflation fluid can be delivered bydevice 100, such as through shaft 110 a and/or 110 b, and/or through aport in expandable assembly 130 and/or expandable assembly 160, such aswhen an associated functional element 139 and/or 169, respectivelycomprises a fluid delivery port attached to a source of insufflationliquid and/or gas (e.g. provided by console 200). Alternatively oradditionally, a separate device configured to be inserted throughendoscope 50 and/or to be positioned alongside endoscope 50, can haveone or more lumens configured to deliver the insufflation fluid. System10 can include one or more occlusive elements and/or devices, such asexpandable assembly 130, expandable assembly 160, occlusive element 193of FIG. 5 and/or another expandable device configured to radially expandsuch as to fully or partially occlude a body lumen, such thatinsufflation pressure can be achieved and/or maintained over time (e.g.reduce or prevent undesired migration of insufflation fluid). The one ormore occlusive elements and/or devices can be positioned proximal toand/or distal to the luminal segment to be insufflated.

Console 200 can be configured to remove fluid from a body lumen such asa segment of the GI tract. Removed fluids include but are not limitedto: tissue expansion fluid; ablative fluid; condensate of deliveredablative fluid; insufflation fluids; excess bodily fluids; chyme;digestive fluids; gas; and combinations of these. Fluids can be removedprior to, during and/or after expansion of target tissue TT by one ormore fluid delivery elements 168 and/or treatment of target tissue TT bytreatment element 135. Treatment element 135, fluid delivery element168, a functional element 139 and/or a functional element 169 can beconstructed and arranged to remove fluid from a body lumen. Console 200can be configured to apply a vacuum (e.g. suction), such as to removefluid via at least one treatment element 135, fluid delivery element168, an outflow drain, or other fluid extraction port of system 10. Insome embodiments, extracted fluids are recycled, such as for subsequentdelivery by at least one treatment element 135 and/or fluid deliveryelement 168 to tissue.

Console 200 can be configured to deliver one or more gases (e.g. carbondioxide, nitrogen, nitrous oxide and/or air) to at least one treatmentelement 135, fluid delivery element 168 and/or another gas deliveringcomponent of system 10. In some embodiments, at least one treatmentelement 135 and/or fluid delivery element 168 comprises a gas jet nozzleconfigured to deliver gas to target tissue, such as a gas than has beenprocessed to remove moisture or otherwise is relatively dry (e.g. lessthan the dew point of air, or at a relative humidity less than 20% orless than 10%). In some embodiments, system 10 is configured to delivergas to cause agitation of an ablative fluid previously delivered withina body lumen. System 10 can be configured to deliver relatively dry orother gas to move ablative fluid in a body lumen. The delivered gas cancomprise a cooling gas, such as a gas below 37° C., a gas between 0° C.and 7° C. such as a gas between 2° C. and 7° C., and/or a gas atapproximately 4° C. System 10 can deliver cooling gas for a time periodof at least 10 seconds, at least 20 seconds or at least 30 seconds. Insome embodiments, system 10 delivers cooling gas at a temperature lessthan 0° C. for a time period less than or equal to 20 seconds, less thanor equal to 10 seconds, or less than or equal to 5 seconds. In someembodiments, system 10 is configured to deliver gas at a temperature ator above 42° C., such as to remove moisture or otherwise dry a tissuewall of the GI tract. System 10 can be configured to deliver carbondioxide gas.

Functional elements 139 and/or 169 can comprise a sensor. In someembodiments, functional element 139 and/or 169, sensor 53 and/or anothersensor of system 10 can comprise a sensor selected from the groupconsisting of: temperature sensor such as a thermocouple, thermistor,resistance temperature detector or an optical temperature sensor; straingauge; impedance sensor such as a tissue impedance sensor; pressuresensor; blood sensor; optical sensor such as a light sensor; soundsensor such as an ultrasound sensor; electromagnetic sensor such as anelectromagnetic field sensor; visual sensor; and combinations of these.The sensors can be configured to provide information to one or morecomponents of system 10, such as to controller 210 and/or console 200,such as to monitor the expansion and/or treatment of target tissue TTand/or to expand and/or treat target tissue TT in a closed loopconfiguration. Fluid delivery by fluid source 220 and/or energy deliveryfrom EDU 250 can be initiated, regulated, modified, stopped and/orotherwise controlled based on one or more sensor readings.

Controller 210 can comprise one or more algorithms 211, which can beconstructed and arranged to automatically and/or manually control and/ormonitor one or more devices, assemblies and/or components of system 10.Algorithm 211 of controller 210 can be configured to determine one ormore tissue expansion and/or tissue treatment parameters. In someembodiments, algorithm 211 processes one or more functional element 139and/or 169 sensor signals to modify one or more of: volume of tissueexpansion fluid delivered; rate of tissue expansion fluid delivery;temperature of tissue expansion fluid delivery; amount of ablative fluiddelivered; rate of ablative fluid delivery; energy delivered; power ofenergy delivered; voltage of energy delivered; current of energydelivered; and/or temperature of ablative fluid or energy delivered.Expandable assembly 130 can deliver energy to a surface of tissue, an“delivery zone”, which is a subset of the target tissue TT treated bythat energy delivery (i.e. due to the conduction of heat or other energyto neighboring tissue). Algorithm 211 can comprise an algorithmconfigured to determine a delivery zone parameter such as a deliveryzone parameter selected from the group consisting of: anatomicallocation of a delivery zone; size of delivery zone; percentage ofdelivery zone to receive energy; type of energy to be delivered to adelivery zone; amount of energy to be delivered to a delivery zone; andcombinations of these. Information regarding the delivery zone parametercan be provided to an operator of system 10. This information can beemployed to set a delivery zone parameter, assist the operator indetermining the completion status of the procedure (e.g. determiningwhen the procedure is sufficiently complete) and/or to advise theoperator to continue to complete a pre-specified area or volume oftarget tissue. The total area of treatment or number of delivery zonesor number of treatments during a particular procedure (any of which canbe employed in algorithm 211) can be defined by patient clinical ordemographic data.

Functional elements 139 and/or 169 can comprise a gravimetric sensor. Insome embodiments, functional element 139 comprises an accelerometer orother sensor configured to provide a signal representing the orientationof expandable assembly 130 and/or treatment element 135 as it relates tothe force of earth's gravity. In embodiments in which treatment element135 delivers ablative fluid to target tissue TT, the signal provided byfunctional element 139 can provide information for manual and/orautomated control of ablative fluid delivery direction. In someembodiments, gravimetric orientation of device 100 is provided to anoperator, such as via a screen on user interface 205 of console 200and/or user interface 105 of handle 102. In some embodiments, the signalfrom functional element 139 is recorded by controller 210, such as toadjust a spray pattern delivered by expandable assembly 130 and/ortreatment element 135, such as via algorithm 211. Based on a signal fromfunctional element 139, treatment element 135 and/or shaft 110 a can bepositioned to deliver ablative fluid in upward and/or side-ways (i.e.horizontal) directions, such as to allow delivered fluid to flow acrossthe walls of a lumen in a downward direction. Controller 210 and/oralgorithm 211 can be configured to adjust the flow pattern of ablativefluid delivery by adjusting the rotation and/or translation ofexpandable assembly 130 (e.g. by creating an asymmetric movement).Controller 210 can be configured to adjust the flow pattern of ablativefluid delivery by adjusting which of multiple treatment elements 135deliver ablative fluid (e.g. by turning on one or more electronic fluidvalves) or by adjusting a nozzle direction or nozzle flow path geometryof treatment element 135 (e.g. when treatment element 135 comprises arotatable nozzle and/or a nozzle with an adjustable orifice). In someembodiments, controller 210 utilizes a signal from functional element139 to manipulate one or more treatment elements 135 to deliver fluid ina relatively upward direction. In some embodiments, system 10 includes afluid removal element as described hereinabove, such as a treatmentelement 135 configured to remove fluid by an outflow drain, and thefluid removal element is gravimetrically oriented by a signal providedby functional element 139.

Functional elements 139 and/or 169 can comprise a chemical detectionsensor, such as a chemical detection sensor to confirm proper appositionof expandable assembly 130 and/or expandable assembly 160. In thisconfiguration, a chemical sensor such as a carbon dioxide sensor can beplaced distal to expandable assembly 130 and/or expandable assembly 160,and a fluid such as carbon dioxide gas can be introduced proximal to theexpandable assembly 130 and/or expandable assembly 160. Detection of theintroduced fluid by a functional element 139 and/or 169 can indicateinadequate apposition of expandable assembly 130 and/or expandableassembly 160, respectively. Readjustment to achieve sufficientapposition can prevent inadequate expansion and/or treatment of targettissue TT (e.g. inadequate delivery of fluid and/or inadequate transferof energy) and/or prevent inadequate measurement, modification,manipulation and/or diagnosis of target tissue TT.

Functional element 139, functional element 169, sensor 53 and/or anothersensor of system 10 can be a sensor configured to provide informationrelated to the tissue treatment and/or expansion performed by expandableassembly 130 and/or expandable assembly 160, respectively, such as avisual sensor mounted to expandable assembly 130 and/or expandableassembly 160 that is configured to differentiate tissue types that areproximate expandable assembly 130 and/or expandable assembly 160. Insome embodiments, system 10 is constructed and arranged to differentiatemucosal and submucosal tissue, such as to adjust one or more treatmentparameters (e.g. to stop treatment and/or modify the temperature oftreatment) based on the differentiation. Applicable visible sensorsinclude but are not limited to: visible light camera; infrared camera;CT Scanner; MRI; and combinations of these. In some embodiments, energyprovided by EDU 250 is based on one or more signals from the visiblesensor, such as a sensor providing a signal correlating to tissue colorwherein the energy delivered is modified based on a tissue color changeand/or tissue expansion injectate 221 comprise a visible dye or othervisualizable marker used to assess tissue expansion.

One or more functional elements 139 and/or 169 can comprise atemperature sensor configured to monitor the temperature of treatmentprovided by expandable assembly 130 and/or expandable assembly 160and/or tissue proximate expandable assembly 130 and/or expandableassembly 160. Functional elements 139 and/or 169 can each comprisemultiple temperature sensors, such as multiple temperature sensorspositioned on expandable assembly 130 and/or expandable assembly 160,respectively, with a spacing of at least one sensor per squarecentimeter. Energy delivered by EDU 250 can be based on signals recordedby the multiple temperature sensors.

Fluid delivered by fluid source 220 (e.g. injectate 221) can be based onsignals recorded by one or functional elements 139 and/or 169. One ormore functional elements 139 and/or 169 can comprise one or moresensors, such as one or more of: a visual sensor such as a camera; atemperature sensor; a pH sensor; an ultrasound transducer; andcombinations of these. In some embodiments, injectate 221 comprises oneor more dyes (e.g. visible dye, ultrasonically visualizable materialand/or radiopaque dye), and functional element 139 and/or 169 comprisesone or more cameras (e.g. visible light camera, ultrasound imager and/orx-ray camera) that image the tissue being expanded and produce a signalcorrelating to the amount of tissue expansion based on the amount of dyepresent in the expanded tissue. In some embodiments, injectate 221 isdelivered at a temperature different than the temperature of the tissuebeing expanded (e.g. above or below body temperature), and functionalelement 139 and/or 169 comprises a sensor that measures the temperatureproximate the tissue being expanded and produces a signal correlating tothe amount of tissue expansion based on the measured temperature (e.g.based on the difference between the measured temperature and bodytemperature). In some embodiments, injectate 221 comprises a pHdifferent than the pH of the tissue being expanded, and functionalelement 139 and/or 169 comprises a sensor that measures the pH proximatethe tissue being expanded and produces a signal correlating to theamount of tissue expansion based on the measured pH (e.g. based on achange in the measured pH that occurs during tissue expansion). In someembodiments, functional element 139 and/or 169 comprises an ultrasoundtransducer directed at the tissue being expanded and produces a signalcorrelating to the amount of tissue expansion based on an analysis of animage of the expanding tissue produced by the ultrasound transducer.

A functional element 139 and/or 169 can comprise a transducer. In theseand other embodiments, functional element 139, functional element 169and/or another transducer of system 10 can be a transducer selected fromthe group consisting of: a heat generating element; a drug deliveryelement such as an iontophoretic drug delivery element; a magnetic fieldgenerator; an ultrasound wave generator such as a piezo crystal; a lightproducing element such as a visible and/or infrared light emittingdiode; a motor; a vibrational transducer; a fluid agitating element; andcombinations of these.

In some embodiments, console 200 and/or another device of component ofsystem 10 is configured to deliver a visualizable material, such as wheninjectate 221 and/or another fluid of system 10 includes a visualizablematerial delivered to one or more fluid delivery elements 168 and/or oneor more treatment elements 135. In some embodiments, visualizablematerial is delivered by fluid delivery element 168 onto and/or beneaththe surface of tissue, to assist in the tissue expansion of targettissue TT, such as to assess the status of tissue expansion as describedhereabove. In some embodiments, visualizable material is delivered bytreatment element 135 onto and/or beneath the surface of tissue, toassist in the treatment of target tissue TT, such as to assess thestatus of tissue ablation, such as via a camera-based functional element139. In some embodiments, the visualizable material is selected from thegroup consisting of; colored dye; radiopaque agent; ultrasonicallyvisible material; magnetically visible material; and combinations ofthese. An imaging device of system 10, such as a camera based functionalelement 139 and/or 169 and/or imaging device 410 described herebelow,can be used to create an image of the visualizable material duringand/or after delivery of the visualizable material.

In some embodiments, console 200 or another device of component ofsystem 10 is configured to deliver abrasive particles, such as abrasiveparticles delivered to one or more treatment elements 135 and/or fluiddelivery elements 168. In some embodiments, visualizable material isalso delivered by console 200 to assist in the treatment of tissue, suchas to improve cellular disruption caused by a mechanical abrasiontreatment by visualizing the treatment in real time.

In some embodiments, EDU 250 is configured to deliver at least RFenergy, and system 10 includes ground pad 70 configured to be attachedto the patient (e.g. on the back of the patient), such that RF energycan be delivered in monopolar delivery mode to one or moreelectrode-based treatment elements 135 of device 100 or to one or moreelectrodes of another device of system 10 (e.g. second device 100′).Alternatively or additionally, EDU 250 can be configured to deliverenergy in a bipolar RF mode, such as bipolar energy delivered betweenany two electrode-based treatment elements 135 of device 100 or betweenany other two electrodes of another treatment device of system 10.Alternatively or additionally, EDU 250 can be configured to deliverenergy in a combined monopolar-bipolar mode.

EDU 250 can be configured to deliver RF and/or other forms of energy toone or more treatment elements 135 of expandable assembly 130 and/or atreatment element of expandable assembly 160. In some embodiments, EDU250 delivers energy selected from the group consisting of: RF energy;microwave energy; plasma energy; ultrasound energy; light energy; andcombinations of these. Energy can be continuous and/or pulsed, and canbe delivered in a closed-loop fashion as described hereabove. Energydelivery parameters such as power, voltage, current and frequency can beheld relatively constant or they can be varied by EDU 250, such as in aclosed loop fashion based on one or more signals provided by asensor-based functional element 139 and/or 169. Energy delivery can bevaried from a first tissue location (e.g. a first portion of targettissue TT) to a second location (e.g. a second portion of target tissueTT), such as a decrease in energy from a first treated location to asecond treated location when the second treated location is thinner thanthe first treated location. Alternatively or additionally, energydelivery can be varied during a single application of energy to a singletissue location, such as by adjusting one or more energy deliveryparameters during a continuous energy delivery. Alternatively oradditionally, one or more energy delivery parameters can be variedbetween a first treatment of target tissue and a second treatment oftarget tissue, for example a first treatment performed during a firstclinical procedure and a second treatment performed during a secondclinical procedure, such as when the second treatment is performed atleast twenty-four hours after the first treatment.

As described hereabove, console 200 typically includes one or more fluidpumps, such as one or more peristaltic, displacement and/or other fluidpumps; as well as one or more heat exchangers and/or other fluid heatingelements internal and/or external to device 100. EDU 250 and/or anothercomponent of console 200 or system 10 can be configured to rapidlydeliver and/or withdraw fluid to and/or from expandable assembly 130and/or expandable assembly 160 via one or more fluid transport means.Fluid transport means can include a pump configured to deliver fluid ata flow rate of at least 50 ml/min and/or a pump and/or vacuum sourceconfigured to remove fluid at a flow rate of at least 50 ml/min. In someembodiments, console 200 is configured to deliver fluid, such as aliquid, at a flow rate of at least 500 ml/min, or at least 750 ml/min. Apump and/or vacuum source can be configured to continuously exchange hotfluid and/or to perform a negative pressure priming event to removefluid from one or more fluid pathways of device 100. Console 200, device100 and/or device 20 can include one or more valves in the fluiddelivery and/or fluid withdrawal pathways or one or more other valves inthe fluid pathway within expandable assembly 130 and/or expandableassembly 160. Valves can be configured to control entry of fluid into anarea and/or to maintain pressure of fluid within an area. Valves can beused to transition from a heating fluid, such as a fluid of 90° C.maintained in a treatment assembly for approximately 12 seconds, to acooling fluid, such as a fluid between 4° C. and 10° C. maintained inthe assembly element for approximately 30 to 60 seconds. Typical valvesinclude but are not limited to: duck-bill valves; slit valves;electronically activated valves; pressure relief valves; andcombinations of these. Console 200 can be configured to rapidly inflateand/or deflate expandable assembly 130 and/or expandable assembly 160.Console 200 can be configured to purge the fluid pathways of device 100and/or device 20 with a gas such as air, such as to remove cold and/orhot fluid from the devices and/or to remove gas bubbles from thedevices.

User interface 205 of console 200 and/or user interface 105 of handle102 can include a graphical user interface configured to allow one ormore operators of system 10 to perform one or more functions such asentering of one or more system input parameters and visualizing and/orrecording of one or more system output parameters. User interface 205and/or user interface 105 can include one or more user input components(e.g. touch screens, keyboards, joysticks, electronic mice and thelike), and one or more user output components (e.g. video displays;liquid crystal displays; alphanumeric displays; audio devices such asspeakers; lights such as light emitting diodes; tactile alerts such asassemblies including a vibrating mechanism; and the like). Examples ofsystem input parameters include but are not limited to: volume of tissueexpanding fluid to be delivered; flow rate of tissue expanding fluid;temperature of tissue expanding fluid; type of tissue expanding fluid tobe delivered; temperature of ablative fluid to be delivered such astemperature of fluid to be delivered to a nozzle or to an expandablereservoir such as a balloon; type of ablative fluid to be delivered;rate of ablative fluid to be delivered; volume of ablative fluid to bedelivered; type of energy to be delivered such as RF energy, thermalenergy and/or mechanical energy; quantity of energy to be delivered suchas a cumulative number of joules of energy to be delivered and/or peakamount of energy to be delivered; types and levels of combinations ofenergies to be delivered; energy delivery duration; pulse widthmodulation percentage of energy delivered; temperature of a coolingfluid to be delivered; temperature of a priming fluid to be delivered;flow rate of a fluid to be delivered; volume of a fluid to be delivered;number of reciprocating motions for an energy delivery element totransverse; temperature for a treatment assembly such as targettemperature and/or maximum temperature; insufflation pressure;insufflation duration; and combinations of these. System inputparameters can include information based on patient anatomy and/orconditions such as pre-procedural and/or peri-procedural parametersselected from the group consisting of: mucosal density and/or thickness;mucosal “lift” off of submucosa after a submucosal injection;longitudinal location of target tissue within the GI tract; andcombinations of these. Examples of system output parameters include butare not limited to: temperature information such as tissue and/ortreatment assembly temperature information; pressure information such asballoon pressure information and/or insufflation pressure information;force information such as level of force applied to tissue information;patient information such as patient physiologic information recorded byone or more sensors; and combinations of these.

Console 200, device 100 and/or one or more other components of system 10can include an electronics module, such as an electronics moduleincluding a processor, memory, software, and the like. User interface205 and/or user interface 105 are typically configured to allow anoperator to initiate, regulate, modify, stop and/or otherwise controlexpansion and/or treatment of target tissue TT by the various componentsof system 10, such as by controlling fluid source 220 and/or EDU 250.User interface 205 and/or user interface 105 can be configured to modifyone or more tissue treatment parameters, such as a parameter selectedfrom the group consisting of: volume of tissue expanding fluid to bedelivered; flow rate of tissue expanding fluid; temperature of tissueexpanding fluid; type of tissue expanding fluid to be delivered;temperature of an ablative fluid to be delivered directly to tissue orto an expandable reservoir such as a balloon; type of ablative fluid tobe delivered; rate of ablative fluid to be delivered; volume of ablativefluid to be delivered; pulse width modulation on-time and/or off-time; atime division multiplexing parameter; and combinations of these. System10 can be configured for manual control, so that the operator firstinitiates the tissue treatment, then allows the treatment element 135and/or another associated treatment element to treat the target tissueTT for some time period, after which the operator terminates thetreatment.

System 10 can be configured to treat target tissue TT in constant,varied, continuous and discontinuous energy delivery or other treatmentdelivery profiles. Pulse width modulation and/or time divisionmultiplexing (TDM) can be incorporated to achieve precision of anablative treatment, such as to ensure ablation of target tissue TT whileleaving non-target tissue intact.

In some embodiments, where system 10 is configured to perform hot fluidablation, controller 210 can be configured to adjust the temperature,flow rate and/or pressure of fluid delivered to an expandable reservoir,such as when expandable assembly 130 and/or expandable assembly 160comprise a balloon. Controller 210 can be configured to receive commandsfrom user interface 205 or user interface 105 of device 100. In someembodiments, controller 210 receives wireless (e.g. Bluetooth) commandsfrom user device 100 via user interface 105. Controller 210 can beconfigured to initiate insufflation and/or to adjust insufflationpressure. Controller 210 can be configured to deliver energy orotherwise treat target tissue in a closed-loop fashion, such as bymodifying one or more tissue treatment parameters based on signals fromone or more sensors of system 10, such as those described hereabove.Controller 210 can be programmable such as to allow an operator to storepredetermined system settings for future use. Controller 210 cancomprise memory configured to store one or more system or patientparameters.

Controller 210 can comprise an impedance monitoring assembly, such as animpedance monitoring assembly that receives impedance information fromone or both of functional element 139 of expandable assembly 130 and/orfunctional element 169 of expandable assembly 160. EDU 250 can deliverRF energy to one or more electrode-based treatment elements of system 10based on the impedance determined by the impedance monitoring assembly.

Numerous embodiments of the systems, methods and devices for treatingtarget tissue TT described hereabove include controlling and/ormonitoring the change in target tissue temperature to cause itsablation, such as a temperature increase above 43° C., typically above60° C., 70° C. or 80° C., to ablate at least a portion of the targettissue TT. One or more cooling fluids can be delivered to limit orotherwise control ablation, such as to prevent damage to non-targettissue, such as the duodenal adventitia. Console 200 can be configuredto deliver a fluid to tissue and/or a component and/or assembly ofsystem 10, such as to warm and/or cool the tissue, component and/orassembly. Console 200 can be configured to deliver a cooling fluid to aluminal wall such as the duodenal wall, such as prior to a delivery ofenergy, during a delivery of energy and/or after a delivery of energy.In some embodiments, a chilled fluid is used to cool tissue prior to,during and/or after a high temperature ablation of tissue. System 10 canbe configured to deliver a fluid at a temperature below 37° C. or below20° C. The chilled fluid can be delivered at a temperature between 0° C.and 7° C., and in some embodiments, the chilled fluid is delivered at atemperature less than 0° C. System 10 to can be configured to deliverchilled fluid at multiple temperatures to target tissue TT and/or othertissue. System 10 can be configured to deliver a first chilled fluid ata first temperature for a first time period, followed by a secondchilled fluid delivered at a second temperature for a second timeperiod. The first and second chilled fluids can be similar or dissimilarfluids, such as similar or dissimilar liquids and/or gases. In someembodiments, the first chilled fluid is colder than the second chilledfluid, such as a first chilled fluid delivered at approximately 4° C.for a time period of approximately 5 seconds, followed by fluiddelivered at a higher temperature (e.g. a temperature between 10° C. and37° C.) for a time period of at least 5 seconds. The chilled fluid canbe delivered between treatment of a first portion of target tissue and asecond portion of target tissue (e.g. to the same or different tissue),such as to remove residual heat remaining after the first treatment. Thecooling fluid can be delivered through functional element 139 ofexpandable assembly 130 and/or functional element 169 of expandableassembly 160, such as when functional elements 139 and/or 169 comprise afluid delivery element such as a nozzle, an exit hole, a slit, or apermeable membrane. The cooling fluid can be supplied to a locationwithin expandable assembly 130 and/or expandable assembly 160, such aswhen expandable assembly 130 and/or expandable assembly 160 comprises aballoon or other expandable reservoir configured to contact tissue.Alternatively or additionally, console 200 can be fluidly attached toanother component of device 100 and/or system 10, the attached componentnot shown but configured to deliver fluid to tissue and/or a componentof system 10 such as to add and/or absorb heat. Console 200 can comprisea cryogenic source used to deliver fluids at low temperatures, such astemperatures below 0° C. Typical fluids delivered include but are notlimited to: liquids such as water and/or saline; gases such as carbondioxide, nitrogen, nitrous oxide and/or air; and combinations of these.

In some embodiments, console 200 includes a desiccant and/or dryingassembly configured to dehydrate or otherwise remove moisture from oneor more delivered gases prior to their delivery by device 100, device 20and/or another device of system 10.

In some embodiments, system 10 and/or device 100 are constructed andarranged to perform a fractional treatment of tissue. Device 100 can beconstructed and arranged to treat target tissue with a fractionaldelivery of RF energy, such as monopolar and/or bipolar RF energydelivered from an array of electrodes positioned on an expandableelement. In some embodiments, device 100 is configured as a laser orother light energy delivery device constructed and arranged to provide afractional energy delivery to target tissue. In some embodiments, device100 is configured to vaporize at least a portion of target tissue.

As described hereabove, system 10 can include one or more additionaltissue expanding and/or tissue treating devices, such as treatmentdevice 100′. Device 100′ and/or other treatment devices of the presentinventive concepts can be configured to treat and/or expand targettissue TT in the same clinical procedure, or in a clinical procedureperformed at least twenty-four hours after the first clinical procedure.Second device 100′ can be of similar or dissimilar construction todevice 100. In some embodiments, second device 100′ comprises anexpandable assembly with a different diameter than expandable assembly130 of device 100. In some embodiments, second device 100′ comprises atreatment element with a different construction and arrangement thantreatment element 135 of device 100. In some embodiments, second device100′ comprises a device selected from the group consisting of: injectatedelivery device; tissue expansion device; hot fluid filled balloondevice; RF energy delivery device; vapor ablation device; cryoablationdevice; laser ablation device; ultrasound ablation device; mechanicalabrasion device; and combinations of these. Second device 100′ cancomprise at least one fluid delivery element selected from the groupconsisting of: needle; fluid jet; iontophoretic element; andcombinations of these. Second device 100′ can comprise at least oneablation element selected from the group consisting of: an RF energydelivery element such as one or more electrodes, each comprising one ormore elongate conductors; an ultrasonic transducer such as one or morepiezo crystals configured to ablate tissue; a laser energy deliveryelement such as one or more optical fibers and/or laser diodes; a heatdelivery element such as a hot fluid filled balloon; a rotating ablationelement; a circumferential array of ablation elements; and combinationsof these.

System 10 can further include one or more imaging devices, such asimaging device 410. Imaging device 410 can be configured to be insertedinto the patient and can comprise a visual light camera; an ultrasoundimager; an optical coherence domain reflectometry (OCDR) imager; and/oran optical coherence tomography (OCT) imager, such as when integral to,attached to, contained within and/or proximate to shaft 110 a and/or 110b. Imaging device 410 can be inserted through a separate working channelof endoscope 50, such as lumen 51. In one embodiment, imaging device 410is an ultrasound transducer connected to a shaft, not shown butsurrounded by shaft 110 a and typically rotated and/or translated tocreate a multi-dimensional image of the area surrounding imaging device410. Alternatively or additionally, imaging device 410 can be externalto the patient, such as an imaging device selected from the groupconsisting of: an X-ray; a fluoroscope; an ultrasound image; an MRI; aPET Scanner; a near-infrared imaging camera; a fluorescence imagingcamera; and combinations of these. Image and other information providedby imaging device 410 can be provided to an operator of system 10 and/orused by a component of system 10, such as controller 210, toautomatically or semi-automatically adjust one or more system parameterssuch as one or more energy delivery parameters.

System 10 can further include protective element 191, configured to bepositioned proximate tissue to prevent damage to certain tissue duringtissue ablative fluid delivery, other energy delivery, tissue expansionand/or other tissue treatment event. Protective element 191 can comprisean element selected from the group consisting of: a deployable and/orrecoverable cap and/or covering; an advanceable and/or retractableprotective sheath; and combinations of these. Protective element 191 canbe delivered with endoscope 50 and/or another elongate device such thatprotective element 191 can be placed over or otherwise positioned toprotect non-target tissue, such as tissue selected from the groupconsisting of: ampulla of Vater; bile duct; pancreas; pylorus;muscularis externae; serosa; and combinations of these. In someembodiments, protective element 191 is placed prior to treatment of atleast a portion of target tissue TT, and removed in the same clinicalprocedure. In other embodiments, protective element 191 is implanted ina first clinical procedure, and removed in a second clinical procedure,such as a second clinical procedure as described herein. In someembodiments, protective element 191 is evacuated from the body by thepatient's digestive system. System 10 can be configured to identifynon-target tissue, such as via a camera used to identify the ampulla ofVater.

System 10 can be configured to prevent excessive or otherwise undesireddistension of the duodenum such as distension that could cause tearingof the serosa. In some embodiments, system 10 is configured such thatall tissue contacting components and/or fluids delivered by system 10maintain forces applied on a GI wall below 2.0 psi, such as less than1.2 psi. System 10 can be configured to avoid or otherwise minimizedamage to the muscularis layer of the GI tract, such as by controllingpressure of target tissue treatment (e.g. via controlling expansionforce of expandable assembly 130 and or expandable assembly 160) and/orby otherwise minimizing trauma imparted on any tissue by one or morecomponents of system 10.

System 10 can further include one or more pharmaceutical and/or otheragents 420, such as an agent configured for systemic and/or localdelivery to a patient. Agents 420 can be delivered pre-procedurally,pen-procedurally and/or post-procedurally. Agents 420 can comprise oneor more imaging agents, such an imaging agent used with imaging device410. Agents 420 can be one or more pharmaceutical or agents configuredto improve healing, such as agents selected from the group consistingof: antibiotics; steroids; mucosal cytoprotective agents such assucralfate, proton pump inhibitors and/or other acid blocking drugs; andcombinations of these. Alternative or in addition to agents 420,pre-procedural and/or post-procedural diets can be employed. Forexample, pre-procedural diets can include food intake that is low incarbohydrates and/or low in calories, and post-procedural diets caninclude food intake that comprise a total liquid diet and/or a diet thatis low in calories and/or low in carbohydrates.

In some embodiments, system 10 does not include a chronically implantedcomponent and/or device, only body inserted devices that are removed atthe end of the clinical procedure or shortly thereafter, such as devicesremoved within 8 hours of insertion, within 24 hours of insertion and/orwithin one week of insertion. In an alternative embodiment, implant 192can be included. Implant 192 can comprise at least one of: a stent; asleeve; and/or a drug delivery device such as a coated stent, a coatedsleeve and/or an implanted pump. Implant 192 can be inserted into thepatient and remain implanted for a period of at least one month, atleast 6 months or at least 1 year. In some embodiments, a first clinicalprocedure is performed treating target tissue, and a subsequent secondclinical procedure is performed, as is described herein. In these twoclinical procedure embodiments, a device can be implanted in the firstclinical procedure, and removed in the second clinical procedure.

System 10 can include sizing device 30 which can be constructed andarranged to be placed into one or more locations of the gastrointestinaltract or other internal location of the patient and measure the size orother geometric parameter of tissue. In some embodiments, sizing device30 has a similar construction and arrangement to sizing device 30 ofFIG. 1. In some embodiments, sizing device 30 comprises a balloon,expandable cage or other sizing element constructed and arranged tomeasure the inner surface diameter of a tubular tissue such as duodenaland/or jejunal tissue. A diameter measurement can be performed byinflating a balloon of sizing device 30 to one or more predeterminedpressures, or pressure profiles, and performing a visualizationprocedure or other procedure to determine balloon diameter.Alternatively or additionally, a balloon can be filled with a fluid andone or more of fluid volume or fluid pressure is measured to determineballoon diameter and subsequently diameter of tubular tissue proximatethe balloon. In some embodiments, subsequent selection (e.g. sizeselection) and/or expansion diameter (e.g. sized for apposition) ofexpandable assembly 130, expandable assembly 160 and/or a treatmentassembly of treatment device 100′ can be determined using these tissuegeometry measurements. Alternatively or additionally, an expandableelement such as a balloon or cage can comprise two or more electrodesconfigured to provide a tissue impedance measurement whose value can becorrelated to a level of apposition of the expandable element, and whoseexpanded diameter (e.g. visually measured) subsequently correlated to adiameter of tubular tissue proximate the expandable element. In someembodiments, expandable assembly 130 and/or expandable assembly 160comprise sizing device 30, such as when expandable assembly 130 and/orexpandable assembly 160 comprise a balloon or other sizing element usedto measure a diameter of the inner surface of tubular tissue.

System 10 can be constructed and arranged to control one or more systemparameters, such as controlling one or more system parameters prior to,during or after the delivery of a thermal dose of energy, during apriming procedure, during a sizing procedure and/or during a tissueexpansion procedure. System 10 can be constructed and arranged tocontrol a system parameter selected from the group consisting of: apriming procedure parameter such as priming temperature or primingduration; a target tissue treatment parameter such as target tissuetemperature or target tissue treatment duration; fluid flow rate such astreatment fluid flow rate; a pressure parameter such as a treatmentelement pressure maintained during treatment of target tissue; atreatment element diameter such as a treatment element diametermaintained during treatment of target tissue; and combinations thereof.System 10 can be constructed and arranged to control the size of anexpandable reservoir, such as by controlling the diameter of expandableassembly 130, expandable assembly 160 and/or another expandablereservoir or assembly as described herein. In some embodiments, a userof system 10 selects a size of an expandable reservoir, such as byselecting the size from a range of available sizes of expandableassembly 130 and/or expandable assembly 160 provided to the user in akit.

Any of the components of system 10 can include a coating, such as alubricious coating. In some embodiments, expandable assembly 130,expandable assembly 160 and/or other radially expandable elements suchas balloons include a lubricious or other material property modifyingcoating. In some embodiments, a radially expandable and radiallycompactable expandable assembly 130 and/or expandable assembly 160comprise a hydrophilic coating, for example configured to disperse orotherwise move an ablative fluid.

Each of the components and/or devices of system 10 can be removablyattached to another component, particularly device 100, device 20,console 200, EDU 250, motion transfer assembly 260, ground pad 70,endoscope 50 and/or second device 100′. Typical attachment means includebut are not limited to mechanical or electromechanical connectorsproviding an electrical, optical and/or fluidic connection between theattached components.

While the preferred embodiments of the devices and methods have beendescribed in reference to the environment in which they were developed,they are merely illustrative of the principles of the inventions.Modification or combinations of the above-described assemblies, otherembodiments, configurations, and methods for carrying out the invention,and variations of aspects of the invention that are obvious to those ofskill in the art are intended to be within the scope of the claims. Inaddition, where this application has listed the steps of a method orprocedure in a specific order, it may be possible, or even expedient incertain circumstances, to change the order in which some steps areperformed, and it is intended that the particular steps of the method orprocedure claim set forth below not be construed as being order-specificunless such order specificity is expressly stated in the claim.

1. (canceled)
 2. A system for modifying tissue to provide a therapeuticbenefit to a patient, the system comprising: a tissue treatment device(100) for treating target tissue comprising: a tissue treatment elementconstructed and arranged to apply a tissue modifying agent to the targettissue, wherein the tissue treatment element is configured to expandprior to the delivery of the tissue modifying agent; and a shaft (110)with a proximal end and a distal portion and a lumen (116), wherein thetissue treatment element is positioned on the distal portion of theshaft (110); a tissue modifying agent delivery unit configured todeliver the tissue modifying agent to the tissue treatment elementthrough the lumen (116); and one or more deployable occluding elements(193) for preventing migration of the tissue modifying agent tonon-target tissue; wherein the one or more deployable occluding elements(193) are positioned within the lumen; a translatable push rod (138)configured to be advanced to deploy the one or more deployable occludingelements (193) from a distal end of the lumen (116); wherein the targettissue comprises duodenal mucosal tissue, and wherein the system isconfigured to modify the target tissue to provide the therapeuticbenefit.
 3. The system according to claim 2, wherein the system isconfigured to treat a cumulative length of duodenal mucosa of at least3.4 cm to achieve the therapeutic benefit.
 4. The system according toclaim 2, wherein the system is configured to treat at least one of adisease or disorder selected from the group consisting of: diabetes;pre-diabetes; impaired glucose tolerance; insulin resistance; obesity orotherwise being overweight; a metabolic disorder; a metabolic disease;and combinations thereof.
 5. The system according to claim 2, whereinthe target tissue comprises duodenal mucosa located distal to theampulla of Vater.
 6. The system according to claim 2, wherein the tissuetreatment device (100) is configured to be inserted through anendoscope.
 7. The system according to claim 2, wherein the tissuetreatment element is configured to expand when contacted with a fluid,optionally wherein the contacting fluid is configured to cause theexpansion comprises the tissue modifying agent.
 8. The system accordingto claim 2, wherein the tissue treatment element is configured to beradially compressed and captured within an endoscope.
 9. The systemaccording to claim 2, wherein the tissue treatment element comprises asponge material.
 10. The system according to claim 9, wherein the spongematerial is selected from the group consisting of: a natural spongematerial; a synthetic sponge material; a foamed polyurethane; apolyvinyl alcohol (PVA) sponge; a hydrogel; a super-absorbent polymer;and combinations thereof.
 11. The system according to claim 2, whereinthe tissue treatment element comprises a balloon, optionally wherein theballoon comprises a permeable balloon, and wherein the tissue modifyingagent is configured to be delivered to the target tissue through thepermeable balloon.
 12. The system according to claim 2, wherein thetissue modifying agent is configured to cause necrosis of the targettissue, optionally wherein the tissue modifying agent is selected fromthe group consisting of: a chemical peeling agent; a mild acid; glycolicacid; trichloroacetic acid; a mild base; phenol; retinoic acid; andcombinations thereof.
 13. The system according to claim 2, furthercomprising a neutralizing agent configured to stop and/or reverse theeffects of the tissue modifying agent.
 14. The system according to claim2, further comprising at least one deployable marker, wherein the targettissue comprises tissue locatable by the at least one marker.
 15. Thesystem according to claim 2, wherein the one or more occluding elementsis/are biodegradable and configured to evacuate the body via the body'snatural digestive system.
 16. The system according to claim 2, whereinthe one or more occluding elements is/are arranged to be removed via agrasping element deployed through an endoscope.